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Recently, it has been shown that blocking the binding of valosin-containing protein (VCP) to mutant huntingtin (mtHtt) can prevent neuronal mitochondrial autophagy in Huntington's disease (HD) models. Herein, we describe the development and efficacy of a protein-like polymer (PLP) for inhibiting this interaction in cellular and in vivo models of HD. PLPs exhibit bioactivity in HD mouse striatal cells by successfully inhibiting mitochondrial destruction. PLP is notably resilient to in vitro enzyme, serum, and liver microsome stability assays, which render analogous control oligopeptides ineffective. PLP demonstrates a 2000-fold increase in circulation half-life compared to peptides, exhibiting an elimination half-life of 152 hours. In vivo efficacy studies in HD transgenic mice (R6/2) confirm the superior bioactivity of PLP compared to free peptide through behavioral and neuropathological analyses. PLP functions by preventing pathologic VCP/mtHtt binding in HD animal models; exhibits enhanced efficacy over the parent, free peptide; and implicates the PLP as a platform with potential for translational central nervous system therapeutics.

An autosomal dominant neurodegenerative disease called Huntington's disease (HD) is characterized by motor dysfunction, cognitive decline, and a variety of psychiatric symptoms due to the expansion of polyglutamine in the Huntingtin gene. The disease primarily affects the striatal neurons within the basal ganglia, leading to significant neuronal loss and associated symptoms such as chorea and dystonia. Current therapeutic approaches focus on symptom management without altering the disease's progression, highlighting a pressing need for novel treatment strategies. Recent studies have identified imidazoline receptors (IRs) as promising targets for neuroprotective and disease-modifying interventions in HD. IRs, particularly the I1 and I2 subtypes, are involved in critical physiological processes such as neurotransmission, neuronal excitability, and cell survival. Activation of these receptors has been shown to modulate neurotransmitter release and provide neuroprotective effects in preclinical models of neurodegeneration. This review discusses the potential of IR-targeted therapies to not only alleviate multiple symptoms of HD but also possibly slow the progression of the disease. We emphasize the necessity for ongoing research to further elucidate the role of IRs in HD and develop selective ligands that could lead to effective and safe treatments, thereby significantly improving patient outcomes and quality of life., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Quinic acid (QA), a cyclitol and cyclohexanecarboxylic acid, is a natural product that is present and can be isolated from edible herbals like tea, coffee and several fruits and vegetables. It was previously reported that QA exerted antioxidant and neuroprotective activity against dementia. However, it was not tested for its neuroprotective potential against Huntington's disease (HD). Since aging related disorders are greatly linked to oxidative stress conditions, we focused on testing the oxidative stress resistant activity and protective effect of QA against the development of HD by using the multicellular Caenorhabditis elegans (C. elegans) worm model., Methods: Firstly, QA was tested for its oxidative stress resistant properties. In survival assay, wild type and mutant skn-1 and daf-16 worms were exposed to oxidative stress conditions by using H 2 O 2 . Activation of SKN-1 pathway and expression of its downstream genes gcs-1 and gst-4 were also tested. Secondly, the effect of QA was evaluated on HD by testing its ability to decrease the formation of polyQ150 aggregates. Furthermore, its effect on the accumulation of polyglutamine (polyQ35 and polyQ40 aggregates) was tested., Results: Here we report that QA could improve the survival of C. elegans after exposure to oxidative stress caused by H 2 O 2 while also exerting antioxidant effects through the activation of SKN-1/Nrf2 pathway. Moreover, QA could be a potential candidate to protect against HD due to its effects on decreasing the formation of polyQ150, polyQ35 and polyQ40 aggregates., Conclusions: This study highlights the importance of QA as a natural compound in defending against oxidative stress and the development of neurodegenerative diseases like HD., (© 2024. The Author(s).)

Background: Anecdotal evidence suggests paradoxical caffeine overuse in individuals with Huntington's disease (HD). A small retrospective study associated caffeine intake over 190 grams daily to earlier onset of HD symptoms. However, specific data on consumption habits is limited. This study aims to gather pilot data on caffeine use in people with HD, exploring motivations and consequences., Methods: Thirty adults with HD completed a survey on daily caffeine intake, its impact on symptoms, and consumption motivations through multiple-choice and open-ended questions. Descriptive statistics were used to analyze findings and compare them to general population data., Results: Caffeine intake ranged from 0 to 1400.4 mg/day, with a median of 273.2 mg/day and a mean of 382.5 mg/day. Seventy percent of participants with HD consumed more caffeine than the average for their age group in the general population. Additionally, 20% of participants and 38% of family members believed caffeine influenced HD symptoms, primarily anxiety., Discussion: People with HD typically consume more caffeine than the general U.S. population. Contrary to the hypothesis, higher caffeine intake was not associated with significant subjective worsening of HD symptoms. Further research with objective measures and multiple HD centers is necessary to guide screening and counseling on caffeine use in this population., Highlights: Participants with Huntington's disease (HD) had increased caffeine intake compared to the general population, supporting previous anecdotal observations. Anxiety was the most affected HD symptom. Further research using objective measures of symptom burden and including multiple HD centers can help inform screening and counseling regarding caffeine use in this population., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by cognitive, motor, and psychiatric symptoms. Despite significant advances in understanding the underlying molecular mechanisms of HD, there is currently no cure or disease-modifying treatment available. Emerging pharmacological approaches offer promising strategies to alleviate symptoms and slow down disease progression. This comprehensive review aims to provide a critical appraisal of the latest developments in pharmacological interventions for HD. The review begins by discussing the pathogenesis of HD, focusing on the role of mutant huntingtin protein, mitochondrial dysfunction, excitotoxicity, and neuro-inflammation. It then explores emerging therapeutic targets, including the modulation of protein homeostasis, mitochondrial function, neuro-inflammation, and neurotransmitter systems. Pharmacological agents targeting these pathways are discussed, including small molecules, gene-based therapies, and neuroprotective agents. In recent years, several clinical trials have been conducted to evaluate the safety and efficiency of novel compounds for HD. This review presents an update on the outcomes of these trials, highlighting promising results and challenges encountered. Additionally, it discusses the potential of repurposing existing drugs approved for other indications as a cost-effective approach for HD treatment. The review concludes by summarizing the current state of pharmacological approaches for HD and outlining future directions in drug development. The integration of multiple therapeutic strategies, personalized medicine approaches, and combination therapies are highlighted as potential avenues to maximize treatment effectiveness., Competing Interests: Declaration of competing interest No conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my-coauthors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Huntington's disease (HD) is a scarce neurodegenerative disorder defined by chorea (unusual involuntary movements), behavioral presentations, psychiatric features, and cognitive deterioration. Although the precise pathogenic mechanism behind HD has not yet been identified, the most widely acknowledged pathways include excitotoxicity, mitochondrial malfunction, neuroinflammation, neurochemical imbalance, oxidative stress, and apoptosis HD has no efficient therapy. Current medications have drawbacks. Silymarin, a compound made up of standardized extracts obtained from the seeds of the Silybum marianum and polyphenolic flavonolignan, is utilized in therapeutic settings to treat a variety of experimental disorders in animals. Silymarin's key pharmacological activities include anti-cancer, hepatoprotection, antioxidant, cardioprotection, and anti-inflammatory. It also has no adverse side effects on people or animals. The current study aims to provide Silymarin's neuro-pharmacological activities or therapeutic qualities in HD. In this study, Thirty-six male Sprague-Dawley rats (200-220 g, 8 weeks) at the initial of the study were used. Silymarin solution (100 mg/Kg) was administered by oral gavage for 21 days to ameliorate neural damage in rats injected with 3-nitropropionicacid (3-NP) in a preliminary rat model of HD. The results showed that administration of silymarin to HD rats reduced gliosis, improved motor coordination and muscle activity, and increased striatal volume and the number of neurons and glial cells. Our results suggest that silymarin provides a protective environment for nerve cells and can have beneficial effects against the harmful effects of HD., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Huntington's disease (HD) is a progressive neurodegenerative disease that causes motor, cognitive, and psychiatric abnormalities, with no satisfying disease-modifying therapy so far. 3-nitropropionic acid (3NP) induces behavioural deficits, together with biochemical and histological alterations in animals' striata that mimic HD. The role of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome in HD pathogenesis remains largely uncharacterized. Parthenolide (PTL), a naturally occurring nuclear factor kappa B (NF-κB) inhibitor, is also known to inhibit NLRP3 inflammasome. Whether PTL is beneficial in HD has not been established yet., Aim: This study evaluated the possible neuroprotective effects of PTL against 3NP-induced behavioural abnormalities, striatal biochemical derangements, and histological aberrations., Methods: Male Wistar rats received PTL (0.5 mg/kg/day, i.p) for 3 weeks and 3NP (10 mg/kg/day, i.p) was administered alongside for the latter 2 weeks to induce HD. Finally, animals were subjected to open-field, Morris water maze and rotarod tests. Rat striata were examined histologically, striatal protein expression levels of glial fibrillary acidic protein (GFAP), cluster of differentiation 45 (CD45) and neuron-specific enolase (NSE) were evaluated immunohistochemically, while those of interleukin (IL)-1β, IL-18, ionized calcium-binding adapter molecule-1 (Iba1) and glutamate were determined by ELISA. Striatal nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein (Keap1), NF-κB, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, S100 calcium-binding protein A10 (S100A10) and complement-3 (C3) were assessed by gene expression analysis., Results: PTL improved motor, locomotor, cognitive and anxiety-like behaviours, restored neuronal integrity, upregulated Nrf2, and inhibited NLRP3 inflammasome, NF-κB and microglial activation. Additionally, PTL induced astrocyte shifting towards the neuroprotective A2 phenotype., Conclusion: PTL exhibits neuroprotection against 3NP-induced HD, that might be ascribed, at least in part, to its modulatory effects on Keap1/Nrf2 and NF-κB/NLRP3 inflammasome signaling., (© 2024. The Author(s).)

Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3) are the two most prevalent polyglutamine (polyQ) neurodegenerative diseases, caused by CAG (encoding glutamine) repeat expansion in the coding region of the huntingtin (HTT) and ataxin-3 (ATXN3) proteins, respectively. We have earlier reported that the activity, but not the protein level, of an essential DNA repair enzyme, polynucleotide kinase 3'-phosphatase (PNKP), is severely abrogated in both HD and SCA3 resulting in accumulation of double-strand breaks in patients' brain genome. While investigating the mechanistic basis for the loss of PNKP activity and accumulation of DNA double-strand breaks leading to neuronal death, we observed that PNKP interacts with the nuclear isoform of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Depletion of PFKFB3 markedly abrogates PNKP activity without changing its protein level. Notably, the levels of both PFKFB3 and its product fructose-2,6 bisphosphate (F2,6BP), an allosteric modulator of glycolysis, are significantly lower in the nuclear extracts of postmortem brain tissues of HD and SCA3 patients. Supplementation of F2,6BP restored PNKP activity in the nuclear extracts of patients' brain. Moreover, intracellular delivery of F2,6BP restored both the activity of PNKP and the integrity of transcribed genome in neuronal cells derived from the striatum of the HD mouse. Importantly, supplementing F2,6BP rescued the HD phenotype in Drosophila, suggesting F2,6BP to serve in vivo as a cofactor for the proper functionality of PNKP and thereby, of brain health. Our results thus provide a compelling rationale for exploring the therapeutic use of F2,6BP and structurally related compounds for treating polyQ diseases., Competing Interests: Competing interests statement:The authors declare no competing interest.

To evaluate the artificial intelligence (AI)-guided AlphaFold algorithm for studying the binding interactions of human huntingtin and the aggregation of huntingtin peptides. Variants of huntingtin protein implicated in Huntington's disease were used as a model system to evaluate AlphaFold. Variants of huntingtin and huntingtin peptides with polyglutamine tracts (PQT) containing 21, 31, 51, or 78 glutamines were studied. The 3-dimensional structures of huntingtin variants and their interactions with huntingtin-associated protein-40 (HAP40) were obtained. Aggregation experiments were conducted with peptide sequences corresponding to variants of PQT, amino terminal sequence (NTS) plus PQT, NTS plus PQT plus proline rich region (PRR), and the 300 amino acid sequence from the NTS through HEAT3 of huntingtin. Oligomerization experiments with 1, 3, 6, or 12 peptide sequences were used to assess the quaternary structures of aggregates. The PQT and PQT plus NTS peptides formed a helical secondary structure that formed a central core in the quaternary structure of the aggregates The PRR formed an extended type II polyproline helix that did not participate in central core the aggregates. The distance between the amino and carboxyl termini of disease-linked 31Q, 51Q, and 78Q variants of full-length huntingtin was prominently decreased compared to the 21Q huntingtin. The interaction of HAP40 with the 78Q variant increased the distance between the amino and carboxyl termini. AlphaFold identified key tertiary structure changes in human huntingtin that have been independently corroborated in experimental models. The results highlight the utility of AlphaFold for hypothesis generation in pharmaceutical research., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Objectives: We conducted a systematic review and meta-analysis to evaluate the clinical effectiveness and safety of riluzole to treat neurodegenerative dyskinesia in patients, using the Cochrane collaboration guidelines., Methods: We searched databases including Medline, Embase, and Cochrane without any language filters. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used as a guideline, and the study protocol was registered in PROSPERO (CRD42022354627)., Results: Eleven studies involving 1376 patients were included. There was a significant overall effect of riluzole on changes in motor function scores. However, the level of heterogeneity was I 2  = 74%. In the subgroup analyses, there were no significant effects of riluzole on motor scores in hereditary ataxia, Parkinson's disease, or Huntington's disease. In the sensitivity analysis, there were no significant effects of riluzole on motor function scores. Furthermore, there were no significant differences in adverse events between the riluzole and placebo groups., Conclusions: Although riluzole may not have significant efficacy for improving motor function in neurodegenerative dyskinesia syndromes compared with placebo, it seems to have an acceptable safety profile. Moreover, it may be effective for hereditary ataxia syndromes, although there was a relatively small effect size and limited quality of evidence., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Aims: The study aimed to evaluate the potential benefits of luteolin treatment in Huntington's disease (HD), an inherited progressive neurodegenerative disorder., Methods: HD N171-82Q transgenic and WT mice received luteolin or vehicle for treatment at 6 weeks of age. The mice's body weight changes and survival rates were monitored throughout the study, and a series of motor functional tests were conducted. Serum level of the marker NfL was also determined. Immunohistochemical staining and western blotting were utilized to assess the expression of huntingtin aggregates., Results: Luteolin treatment enhanced survival and prevented weight loss in HD mice compared to the vehicle-treated HD group. Furthermore, the luteolin-treated HD mice exhibited enhanced motor coordination and balance and significantly reduced motor dysfunction. Also, luteolin decreased serum NfL levels in HD mice. Notably, the accumulation of huntingtin aggregates was significantly reduced in the brain's cortex, hippocampus, and striatum of luteolin-treated HD mice compared to the vehicle-treated HD group., Conclusion: Luteolin holds promise as a therapeutic agent for improving survival outcomes, managing motor dysfunction, and reducing huntingtin aggregates in HD. The findings are of significance as currently, there are no approved therapeutic interventions that reverse HD pathology or slow down its progression., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: Tardive dyskinesia (TD) and Huntington's disease (HD)-associated chorea are persistent and disabling hyperkinetic disorders that can be treated with vesicular monoamine transporter type 2 (VMAT2) inhibitors, including the recently approved once-daily (QD) formulation of deutetrabenazine (DTBZ ER). While its efficacy and safety profile have not been directly investigated, currently available data confirms bioequivalence and similar bioavailability to the twice-daily formulation (DTBZ BID)., Areas Covered: The authors briefly review the pivotal trials establishing efficacy of DTBZ for TD and HD-associated chorea, the pharmacokinetic data for bioequivalence between QD and BID dosing of DTBZ, as well as dose proportionality evidence, titration recommendations, and safety profile for DTBZ ER., Expert Opinion: Long-term data show that DTBZ is efficacious and well tolerated for the treatment of TD and HD-associated chorea. DTBZ ER likely demonstrates therapeutic equivalence with no new safety signals. Due to the lack of comparative clinical trial data, no evidence-based recommendation about choice of VMAT2 inhibitor or switching between VMAT2 inhibitors can be made about best practice. Ultimately, QD dosing may offer the chance of improved medication adherence, an important consideration in patients with complex treatment regimens and/or patients with cognitive decline.

Introduction: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that presents with a progressive movement disorder along with cognitive and psychiatric problems. It is caused by a Cytosine-adenin-guanine (CAG) expansion in exon 1 of the huntingtin gene which codes for mutant huntingtin (mHTT) that over time accumulates in cells, causing dysfunction and then death through new toxic gain-of-function mechanisms. Autophagy has been shown to be critical for the degradation of diverse intracytoplasmic aggregate-prone proteins that cause neurodegenerative disease, including mHTT. From a screen of a library enriched in approved drugs, felodipine was selected as the most suitable candidate showing strong autophagy-inducing effects in preclinical models of HD. We are, therefore, conducting a trial to assess the safety and tolerability of felodipine in people with early HD., Methods and Analysis: FELL-HD is a phase II, single-centre, open-label, dose-finding trial in people with early HD. 18 participants with early clinical features of the disease will be treated with felodipine for 58 weeks, with a further 4-week follow-up. The primary outcome measure is the number of adverse events attributable to felodipine. Exploratory outcomes include additional measures of motor and cognitive function, non-motor symptoms and quality of life scales, as well as peripheral and central disease biomarkers assessed through brain MRI. Analysis of blood and cerebrospinal fluid will also be performed through an associated sample study, FELL HD-s., Ethics and Dissemination: The study was approved by the London-Brent Research Ethics Committee (reference 22/LO/0387) and has been accepted by the Medicines and Healthcare products Regulatory Agency for clinical trials authorisation (reference CTA 12854/0256/001-0001). A lay summary of the results of the trial will be uploaded to our research group website which is publicly accessible. A webinar or in-person open day, to present results of the trial to participants and our wider cohort of patients who attend our centre, will be held once the trial is completed. The results of the trial will also be published in scientific journals and presented at national and international conferences., Trial Registration Numbers: EudraCT-2021-000897-27, ISRCTN56240656., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Purpose of Review: Huntington's disease (HD) is an autosomal-dominant disorder caused by a pathological expansion of a trinucleotide repeat (CAG) on exon 1 of the huntingtin (HTT) gene. HD is characterized by the presence of chorea, alongside other hyperkinesia, parkinsonism and a combination of cognitive and behavioural features. Currently, there are no disease-modifying therapies (DMTs) for HD, and the only intervention(s) with approved indication target the treatment of chorea. This article reviews recent research on the clinical development of DMTs and newly developed tools that enhance clinical trial design towards a successful DMT in the future., Recent Findings: HD is living in an era of target-specific drug development with emphasis on the mechanisms related to mutant Huntingtin (HTT) protein. Examples include antisense oligonucleotides (ASO), splicing modifiers and microRNA molecules that aim to reduce the levels of mutant HTT protein. After initial negative results with ASO molecules Tominersen and WVE-120101/ WVE-120102, the therapeutic landscape continues to expand, with various trials currently under development to document proof-of-concept and safety/tolerability. Immune-targeted therapies have also been evaluated in early-phase clinical trials, with promising preliminary findings. The possibility of quantifying mHTT in CSF, along with the development of an integrated biological staging system in HD are important innovations applicable to clinical trial design that enhance the drug development process. Although a future in HD with DMTs remains a hope for those living with HD, care partners and care providers, the therapeutic landscape is promising, with various drug development programs underway following a targeted approach supported by disease-specific biomarkers and staging frameworks., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Huntington's disease (HD) is a neurodegenerative disorder characterized by cognitive deficits and motor function. Levothyroxine (L-T4) is a synthetic form of Thyroxine (T4), which can improve cognitive ability. The aim of the present study was to determine the neuroprotective effect of L-T4 administration in rats with 3-nitropropionic acid (3-NP)-induced Huntington's disease. Forty-eight Wistar male rats were divided into six groups (n = 8): Group 1 control group that received physiological saline, Group 2 and 3: which received L-T4 (30 and 100 μg/kg), Group 4: HD group that received 3-NP and Groups 5 and 6: The treatment of the HD rats with L-T4 (30 and 100 μg/kg). Spatial memory, locomotor activity, and frequency of neuronal firing were assessed. After decapitation, the Brain-Derived Neurotrophic Factor (BDNF) and Total antioxidant capacity (TAC) levels in the striatum was measured. The results showed that the indices of spatial memory (mean path length and latency time) and motor dysfunction (immobility time) significantly increased, while time spent in the goal quadrant, swimming speed, spike rate, and striatum levels of BDNF significantly decreased in the HD group compared to the control group. L-T4 treatment significantly enhanced time spent in the goal quadrant, swimming speed, motor activity (number of line crossing and rearing), spike rate and striatal BDNF level. This research showed that L-T4 prevented the disruption of motor activity and cognitive deficiencies induced by 3-NP. The beneficial effects of L-T4 may be due to an increase in the concentration of BDNF and enhancement of the spike rate in the striatum., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion in CAG repeat on huntington (Htt) gene, leading to a degeneration of GABAergic medium spiny neurons (MSNs) in the striatum, resulting in the generation of reactive oxygen species, and decrease antioxidant activity. These pathophysiological alterations impair mitochondrial functions, leading to an increase in involuntary hyperkinetic movement. However, researchers investigated the neuroprotective effect of antioxidants using various animal models. Still, their impact is strictly limited to curtailing oxidative stress and increasing the antioxidant enzyme in the brain, which is less effective in HD. Meanwhile, researchers discovered Mitochondria-targeted antioxidants (MTAXs) that can improve mitochondrial functions and antioxidant activity through the modulation of mitochondrial signaling pathways, including peroxisome proliferator-activated receptor (PPAR)-coactivator 1 (PGC-1α), dynamin-related protein 1 (Drp1), mitochondrial fission protein 1 (Fis1), and Silent mating type information regulation 2 homolog 1 (SIRT-1), showing neuroprotective effects in HD. The present review discusses the clinical and preclinical studies that investigate the neuroprotective effect of MTAXs (SS31, XJB-5-131, MitoQ, bezafibrate, rosiglitazone, meldonium, coenzyme Q10, etc.) in HD. This brief literature review will help to understand the relevance of MTAXs in HD and enlighten the importance of MTAXs in future drug discovery and development., (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

The study objectives are to investigate the ability of capsaicin to revert the toxic effects in glutamate and lipopolysaccharide (LPS)-induced neurotoxicity in Neuro2a (N2a) cells as well as thwarting cognitive impairments, mitochondrial deficits, and oxidative insults induced by 3-nitropropanoic acid (3-NP) in a rodent model of Huntington's disease. In-vitro study with N2a cells was performed through MTT and LDH assay and their biochemical examinations were also performed. 3-NP-administered mice (n = 6) were treated with capsaicin (5, 10, and 20 mg/kg) through the per-oral (p.o.) route for 7 consecutive days. Physiological and behavioral studies were performed in drug-treated mice. After behavioral studies, biochemical parameters were performed for cytokines levels, various oxidative stress parameters, and mitochondrial enzyme complex activities with mitochondrial permeability. N2a cells treated with capsaicin demonstrated neuroprotective effects and reduced neurotoxicity. Based on experimental observation, in an in-vitro study, the effective dose of CAP was 50 µM. Moreover, a 100 µM dose of capsaicin had toxic effects on neuronal cells (N2a cells). On the other hand, the effective dose of 3-NP was 20 mg/kg, (p.o.) in animals (in-vivo). All tested doses of capsaicin upturned the cognitive impairment and motor in-coordination effects induced by 3-NP. 3-NP-injected mice demonstrated substantially increased pro-inflammatory cytokine concentrations, defective mitochondrial complex activity, and augmented oxidative insult. However, capsaicin at different doses reduced oxidative damage and cytokines levels and improved mitochondrial complex activity along with mitochondrial permeability. Furthermore, capsaicin (10 and 20 mg/kg) improved the TNF-α concentration. These findings suggested because of the anti-inflammatory and antioxidant effect, capsaicin can be considered a novel treatment for the management of neurodegenerative disorders by reverting the antioxidant enzyme activity, pro-inflammatory cytokines concentration, and mitochondrial functions., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Huntington's disease (HD) is a gradually severe neurodegenerative ailment characterised by an increase of a specific trinucleotide repeat sequence (cytosine-adenine-guanine, CAG). It is passed down as a dominant characteristic that worsens over time, creating a significant risk. Despite being monogenetic, the underlying mechanisms as well as biomarkers remain poorly understood. Furthermore, early detection of HD is challenging, and the available diagnostic procedures have low precision and accuracy. The research was conducted to provide knowledge of the biomarkers, pathways and therapeutic targets involved in the molecular processes of HD using informatic based analysis and applying network-based systems biology approaches. The gene expression profile datasets GSE97100 and GSE74201 relevant to HD were studied. As a consequence, 46 differentially expressed genes (DEGs) were identified. 10 hub genes (TPM1, EIF2S3, CCN2, ACTN1, ACTG2, CCN1, CSRP1, EIF1AX, BEX2 and TCEAL5) were further differentiated in the protein-protein interaction (PPI) network. These hub genes were typically down-regulated. Additionally, DEGs-transcription factors (TFs) connections (e.g. GATA2, YY1 and FOXC1), DEG-microRNA (miRNA) interactions (e.g. hsa-miR-124-3p and has-miR-26b-5p) were also comprehensively forecast. Additionally, related gene ontology concepts (e.g. sequence-specific DNA binding and TF activity) connected to DEGs in HD were identified using gene set enrichment analysis (GSEA). Finally, in silico drug design was employed to find candidate drugs for the treatment HD, and while the possible modest therapeutic compounds (e.g. cortistatin A, 13,16-Epoxy-25-hydroxy-17-cheilanthen-19,25-olide, Hecogenin) against HD were expected. Consequently, the results from this study may give researchers useful resources for the experimental validation of Huntington's diagnosis and therapeutic approaches., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Huntington's disease (HD) is an extremely harmful autosomal inherited neurodegenerative disease. Motor dysfunction, mental disorder, and cognitive deficits are the characteristic features of this disease. The current study examined whether 6-shogaol has a protective effect against 3-Nitropropionic Acid (3-NPA)-induced HD in rats., Methods: A total of thirty male Wistar rats received 6-shogaol (10 and 20 mg/kg, per oral) an hour before injection of 3-NPA (10 mg/kg i.p.) for 15 days. Behavioral tests were performed, including narrow beam walk, rotarod test, and grip strength test. Biochemical tests promoting oxidative stress were evaluated [superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and malondialdehyde (MDA)], including changes to neurotransmitters serotonin (5-HT), dopamine (DA), norepinephrine (NE), homovanillic acid (HVA), (3,4-dihydroxyphenylacetic acid (DOPAC), γ-aminobutyric acid (GABA), and 5-hydroxy indole acetic acid (5-HIAA), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), interleukins-1β (IL-1β), IL-6, brain-derived neurotrophic factor (BDNF), and nuclear factor erythroid 2-related factor 2 (Nrf2). The 6-shogaol was docked to the active site of TNF-α (2AZ5), NF-κB (1SVC), BDNF) [1B8M], and Nrf2 [5FZN] proteins using AutoDock tools., Results: The 6-shogaol group significantly improved behavioral activity over the 3-NPA-injected control rats. Moreover, 3-NPA-induced significantly altered neurotransmitters, biochemical and neuroinflammatory indices, which could efficiently be reversed by 6-shogaol. The 6-shogaol showed favorable negative binding energies at -9.271 (BDNF) kcal/mol., Conclusions: The present investigation demonstrated the neuroprotective effects of 6-shogaol in an experimental animal paradigm against 3-NPA-induced HD in rats. The suggested mechanism is supported by immunohistochemical analysis and western blots, although more research is necessary for definite confirmation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jambi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Gastrodin (GAS) is the main chemical component of the traditional Chinese herb Gastrodia elata (called "Tianma" in Chinese), which has been used to treat neurological conditions, including headaches, epilepsy, stroke, and memory loss. To our knowledge, it is unclear whether GAS has a therapeutic effect on Huntington's disease (HD). In the present study, we evaluated the effect of GAS on the degradation of mutant huntingtin protein (mHtt) by using PC12 cells transfected with N-terminal mHtt Q74. We found that 0.1-100 μM GAS had no effect on the survival rate of Q23 and Q74 PC12 cells after 24-48 h of incubation. The ubiquitin-proteasome system (UPS) is the main system that clears misfolded proteins in eukaryotic cells. Mutated Htt significantly upregulated total ubiquitinated protein (Ub) expression, decreased chymotrypsin-like, trypsin-like and caspase-like peptidase activity, and reduced the colocalization of the 20S proteasome with mHtt. GAS (25 μM) attenuated all of the abovementioned pathological changes, and the regulatory effect of GAS on mHtt was found to be abolished by MG132, a proteasome inhibitor. The autophagy-lysosome pathway (ALP) is another system for misfolded protein degradation. Although GAS downregulated the expression of autophagy markers (LC3II and P62), it increased the colocalization of LC3II with lysosomal associated membrane protein 1 (LAMP1), which indicates that ALP was activated. Moreover, GAS prevented mHtt-induced neuronal damage in PC12 cells. GAS has a selective effect on mHtt in Q74 PC12 cells and has no effect on Q23 and proteins encoded by other genes containing long CAGs, such as Rbm33 (10 CAG repeats) and Hcn1 (>30 CAG repeats). Furthermore, oral administration of 100 mg/kg GAS increased grip strength and attenuated mHtt aggregates in B6-hHTT130-N transgenic mice. This is a high dose (100 mg/kg GAS) when compared with experiments on HD mice with other small molecules. We will design more doses to evaluate the dose-response relationship of the inhibition effect of GAS on mHtt in our next study. In summary, GAS can promote the degradation of mHtt by activating the UPS and ALP, making it a potential therapeutic agent for HD.

N-methyl-D-aspartate receptor (NMDAR)-positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington's disease (HD) and Alzheimer's disease. Dalzanemdor (SAGE-718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first-in-human, phase I, double-blind, dose-finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single-ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple-ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open-label dalzanemdor 1.0 mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once-daily dosing. Following single and multiple doses in healthy participants, median terminal half-life was 8-118 h, and the median time to reach maximum plasma concentration was 4-7 h. Exposures were dose-proportional after single dose (6-46 ng/mL) and more than dose-proportional after multiple doses (6-41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction., (© 2024 Sage Therapeutics, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Protein mislocalization is a key initial step in neurodegeneration, regardless of etiology, and has been linked to changes in the dynamic addition of saturated fatty acids to proteins, a process known as S-acylation. With the advent of new techniques to study S-acylation and the recent discovery of new enzymes that facilitate protein deacylation, novel small molecules are emerging as potential new therapeutic treatments. Huntington disease (HD) is a devastating, fatal neurodegenerative disease characterized by motor, cognitive, and psychiatric deficits caused by a CAG repeat expansion in the HTT gene. The protein that is mutated in HD, huntingtin, is less S-acylated which is associated with mutant HTT aggregation and cytotoxicity. Recent exciting findings indicate that restoring S-acylation in HD models using small molecule inhibitors of the deacylation enzymes is protective. Herein, we set out to describe the known roles of S-acylation in HD and how it can be targeted for therapeutic design., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The neurotoxicity of 3-Nitropropionic acid (3-NP) is well known. Herein, the prophylactic versus therapeutic effects of quercetin (QCT) were investigated against 3-NP-induced behavioral anomalies and oxidative neural damage. Thirty male mice were assigned into five groups; the negative control group, the QCT group (25 mg/kg/day, p.o. for 21 days), the 3-NP group (17 days), the prophylactic group (QCT administration for 14 consecutive days, and then 3-NP was administrated), the therapeutic group (3-NP was administrated and then QCT for 21 days). At the end of the animal treatment, behavioral studies were assessed. Subsequently, the brain sample tissues were assessed for oxidative stress-related parameters and histological evaluation. Moreover, the potential interaction between 3-NP and tumor necrosis factor-alpha (TNF-α) was evaluated by using a molecular docking study. 3-NP markedly led to neurotoxicity which was indicated by behavioral deficits (motor behavior, depression-like behavior, memory dysfunction, and passive avoidance) and oxidative damage. Blind and targeted molecular docking results showed good interaction between 3-NP and TNF-α. However, the prophylactic effects of QCT were superior to the therapeutic effects for attenuating 3-NP-induced neurobehavioral and oxidative neural changes in experimental mice, which histological changes of the brain's striatum region approved our findings. Taken together, the antioxidant activity of QCT remarkably could attenuate 3-NP-induced neurobehavioral deficits and mitochondrial dysfunctions in mice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Huntington's disease (HD) is a progressive neurodegenerative condition characterized by a severe motor incoordination, cognitive decline, and psychiatric complications. However, a definitive cure for this devastating disorder remains elusive. Agmatine, a biogenic amine, has gain attention for its reported neuromodulatory and neuroprotective properties. The present study was designed to examine the influence of agmatine on the behavioral, biochemical, and molecular aspects of HD in an animal model. A mitochondrial toxin, 3-nitro propionic acid (3-NP), was used to induce HD phenotype and similar symptoms such as motor incoordination, memory impairment, neuro-inflammation, and depressive-like behavior in rats. Rats were pre-treated with 3-NP (10 mg/kg, i.p.) on days 1, 3, 5, 7, and 9 and then continued on agmatine treatment (5 - 20 µg/rat, i.c.v.) from day-8 to day-27 of the treatment protocol. 3-NP-induced cognitive impairment was associated with declined in agmatine levels within prefrontal cortex, striatum, and hippocampus. Further, the 3-NP-treated rats showed an increase in IL-6 and TNF-α and a reduction in BDNF immunocontent within these brain areas. Agmatine treatment not only improved the 3-NP-induced motor incoordination, depression-like behavior, rota-rod performance, and learning and memory impairment but also normalized the GABA/glutamate, BDNF, IL-6, and TNF-α levels in discrete brain areas. Similarly, various agmatine modulators, which increase the endogenous agmatine levels in the brain, such as L-arginine (biosynthetic precursor), aminoguanidine (diamine oxidase inhibitor), and arcaine (agmatinase inhibitor) also demonstrated similar effects exhibiting the importance of endogenous agmatinergic pathway in the pathogenesis of 3-NP-induced HD like symptoms. The present study proposed the possible role of agmatine in the pathogenesis and treatment of HD associated motor incoordination, and psychiatric and cognitive complications., Competing Interests: Declaration of Competing Interest Authors declare that there are no conflicts of any interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: PolyQ diseases are autosomal dominant neurodegenerative disorders caused by the expansion of CAG repeats. While of slow progression, these diseases are ultimately fatal and lack effective therapies., Methods: A high-throughput chemical screen was conducted to identify drugs that lower the toxicity of a protein containing the first exon of Huntington's disease (HD) protein huntingtin (HTT) harbouring 94 glutamines (Htt-Q 94 ). Candidate drugs were tested in a wide range of in vitro and in vivo models of polyQ toxicity., Findings: The chemical screen identified the anti-leprosy drug clofazimine as a hit, which was subsequently validated in several in vitro models. Computational analyses of transcriptional signatures revealed that the effect of clofazimine was due to the stimulation of mitochondrial biogenesis by peroxisome proliferator-activated receptor gamma (PPARγ). In agreement with this, clofazimine rescued mitochondrial dysfunction triggered by Htt-Q 94 expression. Importantly, clofazimine also limited polyQ toxicity in developing zebrafish and neuron-specific worm models of polyQ disease., Interpretation: Our results support the potential of repurposing the antimicrobial drug clofazimine for the treatment of polyQ diseases., Funding: A full list of funding sources can be found in the acknowledgments section., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Huntington's Disease (HD) is a genetic neurodegenerative disease for which there is currently no disease-modifying treatment. One of several underlying mechanisms proposed to be involved in HD pathogenesis is inflammation; there is now accumulating evidence that the immune system may play an integral role in disease pathology and progression. As such, modulation of the immune system could be a potential therapeutic target for HD., Areas Covered: To date, the number of trials targeting immune aspects of HD has been limited. However, targeting it, may have great advantages over other therapeutic areas, given that many drugs already exist that have actions in this system coupled to the fact that inflammation can be measured both peripherally and, to some extent, centrally using CSF and PET imaging. In this review, we look at evidence that the immune system and the newly emerging area of the microbiome are altered in HD patients, and then present and discuss clinical trials that have targeted different parts of the immune system., Expert Opinion: We then conclude by discussing how this field might develop going forward, focusing on the role of imaging and other biomarkers to monitor central immune activation and response to novel treatments in HD.

Background: Huntington's disease (HD) is a rare progressive neurological disorder, and telemedicine has the potential to improve the quality of care for patients with HD. Deutetrabenazine (DTBZ) can reduce chorea symptoms in HD; however, there is limited experience with this medication in Asian countries., Methods: Retrospective and prospective studies were employed to explore the feasibility and reliability of a video-based telemedicine system for HD patient care. Reliability was demonstrated through consistency between selected-item scores (SIS) and total motor scores (TMS) and the agreement of scores obtained from hospital and home videos. Finally, a single-centre real-world DTBZ management study was conducted based on the telemedicine system to explore the efficacy of DTBZ in patients with HD., Results: There were 77 patients included in the retrospective study, and a strong correlation was found between SIS and TMS (r = 0.911, P < 0.0001), indicating good representativeness. There were 32 patients enrolled in the prospective study. The reliability was further confirmed, indicated by correlations between SIS and TMS (r = 0.964, P < 0.0001) and consistency of SIS derived from the in-person and virtual visits (r = 0.969, P < 0.0001). There were 17 patients included in the DTBZ study with a mean 1.41 (95% confidence interval, 0.37-2.46) improvement in chorea score and reported treatment success., Conclusions: A video-based telemedicine system is a feasible and reliable option for HD patient care. It may also be used for drug management as a supplementary tool for clinical visits., (© 2023. Fondazione Società Italiana di Neurologia.)

Huntington disease (HD) is a neurodegenerative disorder caused by a mutation in the HTT gene. The expansion of CAG triplets leads to the appearance of misfolded HTT (huntingtin) forming aggregates and leading to impairment of neuronal functions. Here we demonstrate that stimulation of macroautophagy/autophagy by genistein (4',5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4 H-1-benzopyran-4-one) caused a reduction of levels of mutated HTT in brains of HD mice and correction of their behavior as assessed in a battery of cognitive, anxiety and motor tests, even if the compound was administered after symptoms had developed in the animals. Biochemical and immunological parameters were also improved in HD mice. Studies on molecular mechanisms of genistein-mediated stimulation of autophagy in HD cells indicated the involvement of the FOXO3-related pathway. In conclusion, treatment with genistein stimulates the autophagy process in the brains of HD mice, leading to correction of symptoms of HD, suggesting that it might be considered as a potential drug for this disease. Combined with a very recently published report indicating that impaired autophagy may be a major cause of neurodegenerative changes, these results may indicate the way to the development of effective therapeutic approaches for different neurodegenerative diseases by testing compounds (or possibly combinations of compounds) capable of stimulating autophagy and/or unblocking this process. Abbreviations : CNS: central nervous system; EPM: elevated plus-maze; GOT1/ASPAT: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALAT/ALT: glutamic pyruvic transaminase, soluble; HD: Huntington disease; HTT: huntingtin; IL: interleukin; mHTT: mutant huntingtin; NOR: novel object recognition; MWM: Morris water maze; OF: open field; ROS: reactive oxygen species; TNF: tumor necrosis factor.

Huntington's disease (HD) is an inheritable autosomal-dominant disorder that targets mainly the striatum. 3-Nitropropionic acid (3-NP) induces obvious deleterious behavioral, neurochemical, and histological effects similar to the symptoms of HD. Our study aimed to examine the neuroprotective activity of tropisetron, an alpha-7 neuronal nicotinic acetylcholine receptor (α-7nAChR) agonist, against neurotoxic events associated with 3-NP-induced HD in rats. Forty-eight rats were randomly allocated into four groups. Group I received normal saline, while Groups II, III and IV received 3-NP for 2 weeks. In addition, Group III and IV were treated with tropisetron 1 h after 3-NP administration. Meanwhile, Group IV received methyllycaconitine (MLA), an α-7nAChR antagonist, 30 min before tropisetron administration. Treatment with tropisetron improved motor deficits as confirmed by the behavioral tests and restored normal histopathological features of the striatum. Moreover, tropisetron showed an anti-oxidant activity via increasing the activities of SDH and HO-1 as well as Nrf2 expression along with reducing MDA level. Tropisetron also markedly upregulated the protein expression of p-PI3K and p-Akt which in turn hampered JAK2/NF-κB inflammatory cascade. In addition, tropisetron showed an anti-apoptotic activity through boosting the expression of Bcl-2 and reducing Bax expression and caspase-3 level. Interestingly, all the aforementioned effects of tropisetron were blocked by pre-administration of MLA, which confirms that such neuroprotective effects are mediated via activating of α-7nAChR. In conclusion, tropisetron showed a neuroprotective activity against 3-NP-induced HD via activating PI3K/Akt signaling and suppressing JAK2/NF-κB inflammatory axis. Thus, repositioning of tropisetron could represent a promising therapeutic strategy in management of HD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neurodegenerative disorders are devastating disorders characterized by gradual loss of neurons and cognition or mobility impairment. The common pathological features of these diseases are associated with the accumulation of misfolded or aggregation of proteins. The pivotal roles of autophagy and proteostasis in maintaining cellular health and preventing the accumulation of misfolded proteins, which are associated with neurodegenerative diseases like Huntington's disease (HD), Alzheimer's disease (AD), and Parkinson's disease (PD). This article presents an in-depth examination of the interplay between autophagy and proteostasis, highlighting how these processes cooperatively contribute to cellular homeostasis and prevent pathogenic protein aggregate accumulation. Furthermore, the review emphasises the potential therapeutic implications of targeting autophagy and proteostasis to mitigate neurodegenerative diseases. While advancements in research hold promise for developing novel treatments, the article also addresses the challenges and complexities associated with modulating these intricate cellular pathways. Ultimately, advancing understanding of the underlying mechanism of autophagy and proteostasis in neurodegenerative disorders provides valuable insights into potential therapeutic avenues and future research directions., (© 2024 John Wiley & Sons Ltd.)

Huntington's Disease (HD) is a progressive neurodegenerative disease caused by a mutation in the huntingtin gene. The mutation leads to a toxic gain of function of the mutant huntingtin (mHtt) protein resulting in cellular malfunction, aberrant huntingtin aggregation and eventually neuronal cell death. Patients with HD show impaired motor functions and cognitive decline. Elevated levels of glucocorticoids have been found in HD patients and in HD mouse models, and there is a positive correlation between increased glucocorticoid levels and the progression of HD. Therefore, antagonism of the glucocorticoid receptor (GR) may be an interesting strategy for the treatment of HD. In this study, we evaluated the efficacy of the selective GR antagonist CORT113176 in the commonly used R6/2 mouse model. In male mice, CORT113176 treatment significantly delayed the loss of grip strength, the development of hindlimb clasping, gait abnormalities, and the occurrence of epileptic seizures. CORT113176 treatment delayed loss of DARPP-32 immunoreactivity in the dorsolateral striatum. It also restored HD-related parameters including astrocyte markers in both the dorsolateral striatum and the hippocampus, and microglia markers in the hippocampus. This suggests that CORT113176 has both cell-type and brain region-specific effects. CORT113176 delayed the formation of mHtt aggregates in the striatum and the hippocampus. In female mice, we did not observe major effects of CORT113176 treatment on HD-related symptoms, with the exception of the anti-epileptic effects. We conclude that CORT113176 effectively delays several key symptoms related to the HD phenotype in male R6/2 mice and believe that GR antagonism may be a possible treatment option., Competing Interests: Declaration of competing interest Hazel Hunt is an employee and Jan Kroon is seconded at Corcept Therapeutics, the pharmaceutical company that designs and develops CORT113176. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

GPR52 is a highly conserved, brain-enriched, G s/olf -coupled orphan G protein-coupled receptor (GPCR) that controls various cyclic AMP (cAMP)-dependent physiological and pathological processes. Stimulation of GPR52 activity might be beneficial for the treatment of schizophrenia, psychiatric disorders and other human neurological diseases, whereas inhibition of its activity might provide a potential therapeutic approach for Huntington's disease. Excitingly, HTL0048149 (HTL'149), an orally available GPR52 agonist, has been advanced into phase I human clinical trials for the treatment of schizophrenia. In this concise review, we summarize the current understanding of GPR52 receptor distribution as well as its structure and functions, highlighting the recent advances in drug discovery efforts towards small-molecule GPR52 ligands. The opportunities and challenges presented by targeting GPR52 for novel therapeutics are also briefly discussed., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The striatum, an essential component of the brain's motor and reward systems, plays a pivotal role in a wide array of cognitive processes. Its dysfunction is a hallmark of neurodegenerative diseases like Parkinson's disease (PD) and Huntington's disease (HD), leading to profound motor and cognitive deficits. These conditions are often related to excitotoxicity, primarily due to overactivation of NMDA receptors (NMDAR). In the synaptic cleft, glycine transporter type 1 (GlyT1) controls the glycine levels, a NMDAR co-agonist, which modulates NMDAR function. This research explored the neuroprotective potential of NFPS, a GlyT1 inhibitor, in murine models of striatal injury. Employing models of neurotoxicity induced by 6-hydroxydopamine (PD model) and quinolinic acid (HD model), we assessed the effectiveness of NFPS pre-treatment in maintaining the integrity of striatal neurons and averting neuronal degeneration. The results indicated that NFPS pre-treatment conferred significant neuroprotection, reducing neuronal degeneration, protecting dopaminergic neurons, and preserving dendritic spines within the striatum. Additionally, this pre-treatment notably mitigated motor impairments resulting from striatal damage. The study revealed that GlyT1 inhibition led to substantial changes in the ratios of NMDAR subunits GluN2A/GluN1 and GluN2B/GluN1, 24 h after NFPS treatment. These findings underscore the neuroprotective efficacy of GlyT1 inhibition, proposing it as a viable therapeutic strategy for striatum-related damage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Huntington's disease (HD) is a neurodegenerative disorder characterized by degeneration of the striatum; it results in oxidative stress and motor deficits. Thyroid hormones regulate oxidative metabolism. In the present study, we evaluated the effect of administration of levothyroxine (LT-4) on neurobehavioral, oxidative stress, and histological changes in a rat model of HD. Forty-eight Wistar male rats were divided into the following six groups (n = 8): Group 1 (control) received physiological saline intraperitoneally (ip). Groups 2 and 3 received L-T4,30 and L-T4100 (μg/kg, ip, respectively) daily for 7 days. Group 4 (HD) received 3-nitropropionic acid (3-NP) (25 mg/kg, ip) daily for 7 days. Groups 5 and 6 received L-T4,30 and L-T4100 (μg/kg, ip, respectively) 30 min after 3-NP (25 mg/kg, ip) injection for the same duration. On the 8th day, behavioral parameters were evaluated with the Rotarod, Narrow beam walk, and Limb withdrawal tests. Oxidative markers such as Malondialdehyde (MDA) and Glutathione (GSH) levels and Superoxide dismutase (SOD) activity, in striatum tissue were measured. Moreover, striatum tissues were analyzed by Hematoxylin-eosin staining for histological alterations. We found that 3-NP administration caused motor incoordination and induced oxidative stress increased but reduced free radical scavenging. Also, increased amounts of lipid peroxides caused striatal damage as shown by histopathological evaluation. Administration of L-T4 led to increased falling time in the Rotarod, but reduced the time taken in Narrow beam walking and Limb withdrawal test. Furthermore, L-T4 increased antioxidant activity, decreased lipid peroxidation and ameliorated 3-NP-induced degeneration in neurons., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease., Methods: LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21-55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014-000418-75, and is now complete., Findings: Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI -1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference -1·76% [95% CI -2·67 to -0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%])., Interpretation: Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington's disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments., Funding: Teva Pharmaceutical Industries., Competing Interests: Declaration of interests RR is founding director and owner of the George Huntington Institute, a private research institute focused on clinical and preclinical research in Huntington's disease, and QuantiMedis, a clinical research organisation providing Q-Motor services in clinical trials and research. He served as an elected member of the executive committees of the European Huntington's Disease Network and the Huntington's Study Group, and as co-chair of the Task Force on Huntington's Disease of the International Parkinson and Movement Disorder Society. He has provided consulting services to Teva Pharmaceuticals, all payments to institution. He reports receiving payments for clinical trial services (global coordinating principal investigator role, patient recruitment, and quantitative motor assessment) and consulting services from Actelion, Alnylam, Amarin, AOP Orphan Pharmaceuticals, AskBio, Cure Huntington Disease Initiative Foundation, Desitin, Hoffmann-La Roche, IONIS, Ipsen, Lundbeck, MEDA Pharma, Medivation, Mitoconix, Neurocrine, Neurosearch, Novartis, Omeros, Pfizer, Prana Biotechnology, Prilenia, PTC Therapeutics, Raptor, Sage, Siena Biotech, Solaxa, Temmler Pharma, Teva, uniQure, Vaccinex, Voyager, Wave Life Sciences, and Zevra, all payments to institution. KEA reports that salary support was paid by Teva to her institution, Georgetown University, for work as co-principal investigator for North American sites, and that she has received honoraria from Teva for giving lectures and participation in advisory boards. She is also a paid consultant to Novartis Pharmaceuticals, Azevan Pharmaceuticals, Cure Huntington Disease Initiative Foundation, the Lundbeck Foundation, and Neurocrine Pharmaceuticals. She receives salary support, paid to her institution, from the Griffin Foundation and the Huntington Study Group. She receives salary support, paid to her institution, as a site investigator for clinical trials for SAGE Pharmaceuticals and Prilenia Pharmaceuticals. She has received salary support, paid to her institution, as a site investigator for observational studies from Cure Huntington Disease Initiative Foundation. AF served as chair of the Huntington Study Group from 2018 to 2022. He is on the data and safety monitoring board for Alzheimer's Disease Cooperative Study/Alzheimer's Therapeutic Research Institute and chairs a data and safety monitoring board for PTC Therapeutics. He has received institutional grant support to New York University, as a co-principal investigator of the LEGATO-HD study. He has also received grants to his institution, New York University, from Prilenia Therapeutics and the Huntington Study Group, and consulting fees from AskBio and Annexon. SJT reports receiving a research contract from Teva Pharmaceuticals to run LEGATO-HD at the University College London Hospital site. SJT reports receiving grant support from the following groups: the Cure Huntington Disease Initiative Foundation, Vertex Pharmaceuticals, UK Medical Research Council, Wellcome Trust, and UK Dementia Research Institute. SJT reports that consultancy fees for advisory services were paid to University College London Consultants, a wholly-owned subsidiary of University College London from the following companies: F Hoffman LaRoche, Annexon Biosciences, PTC Therapeutics, Takeda Pharmaceuticals, Vertex Pharmaceuticals, Alnylam Pharmaceuticals, Genentech, LoQus23 Therapeutics, Triplet Therapeutics, Novartis, Atalanta, Spark Therapeutics, Horama, University College Irvine, Rgenta Therapeutics, Locanobio, Adrestia Therapeutics, Alchemab, Biogen, Design Therapeutics, HCD Economics, Ipsen Bioscience, Iris Medicine, Latus Therapeutics/8V, Life Edit Therapeutics, Pfizer, Prilenia Therapeutics, Regeneron Pharmaceutics, Remix Therapeutics, Sanofi, and Unique. SJT reports consulting fees and advisory services with payment directly to SJT from Alphasight, Guidepoint, and Iqvia, and reports a patent issued on application number 2105484·6, 25 licensed to Adrestia Therapeutics. BRL reports grant support from Teva Pharmaceuticals to his university, University of British Columbia, as a site for LEGATO-HD. BRL reports receiving grant support to his university, University of British Columbia, from the following groups: Huntington Society of Canada, Canadian Institutes of Health Research, and NanoMedicines Innovation Network. BRL reports receiving consulting fees as a scientific consultant from the following companies: uniQure, Teva Pharmaceuticals, Takeda, Triplet, Novartis, PTC, Remix, LifeEdit, Spark, Design, Scientetica, Roche/Genentech, and Camp4, and reports many patents with University of British Columbia and Incisive Genetics. BRL is chief executive officer, board member, and co-founder of Incisive Genetics, a biotech startup, and holds stock in this company. BRL has participated on the scientific advisory board for sRNAlytics and has received stock options. He is co-editor-in-chief of the Journal of Huntington's Disease, an unpaid position which receives some expense reimbursement. JCS was director of Stout Neuropath (now Zindametrix), a commercial research service that provided assistance in implementing the HD-CAB for the LEGATO-HD study. Stout Neuropath neuropsychology staff were masked to participant group assignment during the LEGATO-HD study. PP reports receiving grant support from Cure Huntington Disease Initiative Foundation, Parkinson's UK, the UK Medical Research Council, and the Michael J Fox Foundation. RS is an employee of the George Huntington Institute, a private research institute focused on clinical and preclinical research in Huntington's disease, and QuantiMedis, a clinical research organisation providing Q-Motor services in clinical trials and research. PL, GR, RV, TL, and MFG are employees of Teva Pharmaceuticals and own stock. AW is a former employee of Teva Pharmaceuticals and current employee of Novo Nordisk. BB is a former employee of Teva Pharmaceuticals and current employee of Novartis Pharmaceuticals. J-MS is a former employee of Teva Pharmaceuticals and current employee of Spark Therapeutics. MH is the former head of Teva Global Research and Development and is currently the founder and chief executive officer of Prilenia Therapeutics., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Huntington's disease (HD) is an incurable inherited disorder caused by a repeated expansion of glutamines in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological symptoms. Selective downregulation of the mutant Htt gene expression is considered the most promising therapeutic approach for HD. We report the identification of small molecule inhibitors of Spt5-Pol II, SPI-24 and SPI-77, which selectively lower mutant Htt mRNA and protein levels in HD cells. In the BACHD mouse model, their direct delivery to the striatum diminished mutant Htt levels, ameliorated mitochondrial dysfunction, restored BDNF expression, and improved motor and anxiety-like phenotypes. Pharmacokinetic studies revealed that these SPIs pass the blood-brain-barrier. Prolonged subcutaneous injection or oral administration to early-stage mice significantly delayed disease deterioration. SPI-24 long-term treatment had no side effects or global changes in gene expression. Thus, lowering mutant Htt levels by small molecules can be an effective therapeutic strategy for HD., (© 2024. The Author(s).)

Introduction: Being an inherited neurodegenerative disease with an identifiable genetic defect, Huntington's disease (HD) is a suitable candidate for early intervention, possibly even in the pre-symptomatic stage. Our recent advances in elucidating the pathogenesis of HD have revealed a series of novel potential therapeutic targets, among which immunotherapies are actively pursued in preclinical experiments., Areas Covered: This review focuses on the potential of antibody-based treatments targeting various epitopes (of mutant huntingtin as well as phosphorylated tau) that are currently evaluated in vitro and in animal experiments. The references used in this review were retrieved from the PubMed database, searching for immunotherapies in HD, and clinical trial registries were reviewed for molecules already evaluated in clinical trials., Expert Opinion: Antibody-based therapies have raised considerable interest in a series of neurodegenerative diseases characterized by deposition of aggregated of aberrantly folded proteins, HD included. Intrabodies and nanobodies can interact with mutant huntingtin inside the nervous cells. However, the conflicting results obtained with some of these intrabodies highlight the need for proper choice of epitopes and for developing animal models more closely mimicking human disease. Approval of these strategies will require a considerable financial and logistic effort on behalf of healthcare systems.

Efficient delivery of therapeutics to the central nervous system (CNS) remains a major challenge for the treatment of neurological diseases. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion mutation in the HTT gene which codes for a toxic mutant huntingtin (mHTT) protein. Pharmacological reduction of mHTT in the CNS using antisense oligonucleotides (ASO) ameliorates HD-like phenotypes in rodent models of HD, with such therapies being investigated in clinical trials for HD. In this study, we report the optimization of apolipoprotein A-I nanodisks (apoA-I NDs) as vehicles for delivery of a HTT-targeted ASO (HTT ASO) to the brain and peripheral organs for HD. We demonstrate that apoA-I wild type (WT) and the apoA-I K133C mutant incubated with a synthetic lipid, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, can self-assemble into monodisperse discoidal particles with diameters <20 nm that transmigrate across an in vitro blood-brain barrier model of HD. We demonstrate that apoA-I NDs are well tolerated in vivo, and that apoA-I K133C NDs show enhanced distribution to the CNS and peripheral organs compared to apoA-I WT NDs following systemic administration. ApoA-I K133C conjugated with HTT ASO forms NDs (HTT ASO NDs) that induce significant mHTT lowering in the liver, skeletal muscle and heart as well as in the brain when delivered intravenously in the BACHD mouse model of HD. Furthermore, HTT ASO NDs increase the magnitude of mHTT lowering in the striatum and cortex compared to HTT ASO alone following intracerebroventricular administration. These findings demonstrate the potential utility of apoA-I NDs as biocompatible vehicles for enhancing delivery of mutant HTT lowering ASOs to the CNS and peripheral organs for HD., Competing Interests: Declaration of competing interest N.S.C. is a scientific consultant for GLG. D.D.O.M. is a scientific advisor for Circumvent Pharmaceuticals, Inc. M.N.O. is a scientific consultant for CymaBay Therapeutics. M.N.O. is the founder and CTO of Lipotope, Inc. B.R.L. is a scientific consultant for sRNAlytics, Teva, Roche/Genentech, Takeda, Triplet, Ionis Pharmaceuticals, Novartis, Spark Therapeutics, Sintetica, LifeEdit, Design Therapeutics, Remix Therapeutics, and PTC Therapeutics. B.R.L. is a founder and CEO of Incisive Genetics Inc. M.R.H. is the CEO of Prilenia Therapeutics, a private company, and serves on the public boards of Ionis Pharmaceuticals, Oxford Biomedica, AbCellera and 89bio. The other authors report there are no competing interests to declare., (Copyright © 2023. Published by Elsevier B.V.)

Competing Interests: TAM reports speaker honorarium from Abbvie and International Parkinson and Movement Disorder Society; consultancies from CHDI Foundation/Management, Roche, and Abbvie; and research funding from EU Joint Programme—Neurodegenerative Disease Research, uOBMRI, Roche, Ontario Research Fund, Canadian Institutes of Health Research, The Michael J Fox Foundation, Parkinson Canada, and Parkinson Research Consortium.

Introduction: There is an urgent need for new or repurposed therapeutics that protect against or significantly delay the clinical progression of neurodegenerative diseases, such as Huntington's disease (HD), Parkinson's disease and Alzheimer's disease. In particular, preclinical studies are needed for well tolerated and brain-penetrating small molecules capable of mitigating the proteotoxic mitochondrial processes that are hallmarks of these diseases. We identified a unique suicide inhibitor of mitochondrial proline dehydrogenase (Prodh), N-propargylglycine (N-PPG), which has anticancer and brain-enhancing mitohormesis properties, and we hypothesize that induction of mitohormesis by N-PPG protects against neurodegenerative diseases. We carried out a series of mouse studies designed to: i) compare brain and metabolic responses while on oral N-PPG treatment (50 mg/kg, 9-14 days) of B6CBA wildtype (WT) and short-lived transgenic R6/2 (HD) mice; and ii) evaluate potential brain and systemwide stress rebound responses in WT mice 2 months after cessation of extended mitohormesis induction by well-tolerated higher doses of N-PPG (100-200 mg/kg x 60 days). WT and HD mice showed comparable global evidence of N-PPG induced brain mitohormesis characterized by Prodh protein decay and increased mitochondrial expression of chaperone and Yme1l1 protease proteins. Interestingly, transcriptional analysis (RNAseq) showed partial normalization of HD whole brain transcriptomes toward those of WT mice. Comprehensive metabolomic profiles performed on control and N-PPG treated blood, brain, and kidney samples revealed expected N-PPG-induced tissue increases in proline levels in both WT and HD mice, accompanied by surprising parallel increases in hydroxyproline and sarcosine. Two months after cessation of the higher dose N-PPG stress treatments, WT mouse brains showed robust rebound increases in Prodh protein levels and mitochondrial transcriptome responses, as well as altered profiles of blood amino acid-related metabolites. Our HD and WT mouse preclinical findings point to the brain penetrating and mitohormesis-inducing potential of the drug candidate, N-PPG, and provide new rationale and application insights supporting its further preclinical testing in various models of neurodegenerative diseases characterized by loss of mitochondrial proteostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Huntington's disease (HD) is an autosomal neurodegenerative disease that involves movement disorders, cognitive impairments, and psychiatric symptoms. It is characterized by regionally selective cortical degeneration that proceeds from posterior to anterior cortical region which explains its heterogeneity. At present, the psychiatric symptoms of HD are mostly managed by antidepressant such as selective serotonin reuptake inhibitors or selective nor-epinephrine reuptake inhibitors, and atypical antipsychotics. Currently, there are no efficient pharmacological treatment available for HD. Thus, in order to avoid this void in effective pharmacotherapy, further supplemental and alternative approaches are being explored for the management of problems associated with HD. A literature review was performed using the databases PubMed and Google Scholar identifying clinical studies that were set to ameliorate the symptoms associated with HD. On critical analysis, it was found that alternative treatment modalities like music therapy, video games, Yoga, Physical therapy, and exercise-based programs have a potential and possible role in improving the symptoms of HD at varied degrees.

Huntington disease (HD) is a hereditary neurodegenerative disorder with a hallmark feature of chorea. While no disease-modifying therapies currently exist for HD, symptomatic treatment of HD-associated chorea includes US Food and Drug Administration-approved vesicular monoamine transporter type 2 inhibitors-tetrabenazine and deutetrabenazine. Deutetrabenazine was more recently approved (2017), and while structurally similar to tetrabenazine, deutetrabenazine has a unique pharmacokinetic profile that allows for a longer half-life, reduced plasma fluctuations, and less frequent dosing. In pivotal trials, deutetrabenazine seemed to have an improved safety and tolerability profile over tetrabenazine but real-world data to confirm this are lacking. Here, we evaluate our real-world clinical experience with deutetrabenazine for HD-associated chorea. We performed a retrospective chart review of all patients with HD who initiated treatment with deutetrabenazine from January 2017 to May 2019 at the University of Alabama at Birmingham. Total maximal chorea scores, patient-reported subjective efficacy, dosing information, and subjective reports of adverse events (AEs) were abstracted for each patient. Our review included 58 patients with a mean length of treatment of 476.4 days. In the reviewed time period, the mean treatment difference in total maximal chorea scores was 4.4. The combined total rate of occurrence of any AEs was relatively low, at 32.8%, and the most commonly reported AEs were sedation (15.5%), insomnia (6.9%), and diarrhea (3.4%). Our real-world data support current literature indicating that deutetrabenazine is an effective and well-tolerated treatment for HD-associated chorea. Further studies repeating this on a larger scale, across a greater geography and practice pattern, are needed., (© 2023, The American College of Clinical Pharmacology.)

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by a mutation in the huntingtin (HTT) gene, resulting in the production of a mutant huntingtin protein (mHTT). The accumulation of mHTT leads to the development of toxic aggregates in neurons, causing cell dysfunction and, eventually, cell death. Peptide therapeutics target various aspects of HD pathology, including mHTT reduction and aggregation inhibition, extended CAG mRNA degradation, and modulation of dysregulated signaling pathways, such as BDNF/TrkB signaling. In addition, these peptide therapeutics also target the detrimental interactions of mHTT with InsP3R1, CaM, or Caspase-6 proteins to mitigate HD. This Perspective provides a detailed perspective on anti-HD therapeutic peptides, highlighting their design, structural characteristics, neuroprotective effects, and specific mechanisms of action. Peptide therapeutics for HD exhibit promise in preclinical models, but further investigation is required to confirm their effectiveness as viable therapeutic strategies, recognizing that no approved peptide therapy for HD currently exists.

Aims: This study evaluated the association between provider types for patients with newly diagnosed Huntington's disease (HD) and healthcare resource utilization (HCRU), costs, and treatment patterns., Materials and Methods: This retrospective analysis used MarketScan databases (1 January 2017-31 December 2021) to identify provider types who diagnosed and managed US adult patients with HD. Patients with continuous enrollment 6 months pre- and 12 months post-diagnosis were included. Outcomes evaluated over 12 months post-diagnosis included hospitalizations, outpatient visits, antipsychotic or vesicular monoamine transporter 2 (VMAT2) inhibitor use, and total healthcare costs., Results: Three hundred and forty eligible patients had a mean age at diagnosis of 49 years. 56.5% were female; 71.5% had a Charlson Comorbidity Index of 0. Patients were diagnosed by neurologists (48.5%), primary care providers (PCPs) (35.6%), psychiatrists (3.5%), or other providers (12.4%). Patients diagnosed by PCPs or neurologists received significantly more follow-ups by the same diagnosing provider type ( p  < 0.05). All-cause and HD-related outpatient visits at 12-month follow-up had more patients diagnosed by PCPs (23.9, 5.1) than neurologists (18.0, 2.4), psychiatrists (16.7, 1.67), or others (15.3, 2.4). HD-related mean costs totaled $2,489 ($1,179 inpatient and $1,310 outpatient). Patients diagnosed by neurologists had significantly lower HD-related total non-medication costs vs. those diagnosed by PCPs (-$2,256; p  < 0.05). Among patients diagnosed by neurologists vs. PCPs, similar proportions received antipsychotics within the first year (55 vs. 52%, respectively); more patients managed by neurologists received VMAT2 inhibitors (12 vs. 7%, respectively)., Limitations: Our study includes limitations inherent to retrospective claims studies., Conclusions: Patients with HD are most often diagnosed by neurologists or PCPs; the same diagnosing provider type typically manages follow-up. Patients diagnosed by neurologists had significantly fewer HD-related outpatient visits, lower HD-related non-drug costs, and more frequently received VMAT2 inhibitors vs. those diagnosed by PCPs. Our findings show an integrated care team may provide evidence-based, personalized care for patients with HD.

Neurodegenerative disorders, which include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a significant and growing global health challenge. Current therapies predominantly focus on symptom management rather than altering disease progression. In this review, we discuss the major therapeutic strategies in practice for these disorders, highlighting their limitations. For AD, the mainstay treatments are cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. For PD, dopamine replacement therapies, including levodopa, are commonly used. HD is managed primarily with symptomatic treatments, and reusable extends survival in ALS. However, none of these therapies halts or substantially slows the neurodegenerative process. In contrast, this review highlights emerging research into bioactive peptides as potential therapeutic agents. These naturally occurring or synthetically designed molecules can interact with specific cellular targets, potentially modulating disease processes. Preclinical studies suggest that bioactive peptides may mitigate oxidative stress, inflammation, and protein misfolding, which are common pathological features in neurodegenerative diseases. Clinical trials using bioactive peptides for neurodegeneration are limited but show promising initial results. For instance, hemiacetal, a γ-secretase inhibitor peptide, has shown potential in AD by reducing amyloid-beta production, though its development was discontinued due to side effects. Despite these advancements, many challenges remain, including identifying optimal peptides, confirming their mechanisms of action, and overcoming obstacles related to their delivery to the brain. Future research should prioritize the discovery and development of novel bioactive peptides and improve our understanding of their pharmacokinetics and pharmacodynamics. Ultimately, this approach may lead to more effective therapies for neurodegenerative disorders, moving beyond symptom management to potentially modify the course of these devastating diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD., Objective: The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent., Methods: Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NP + PNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis., Results: Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity., Conclusions: Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.