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Dendrite defects and loss are early cellular alterations observed across neurodegenerative diseases that play a role in early disease pathogenesis. Dendrite degeneration can be modeled by expressing pathogenic polyglutamine disease transgenes in Drosophila neurons in vivo. Here, we show that we can protect against dendrite loss in neurons modeling neurodegenerative polyglutamine diseases through injury to a single primary dendrite branch. We find that this neuroprotection is specific to injury-induced activation of dendrite regeneration: neither injury to the axon nor injury just to surrounding tissues induces this response. We show that the mechanism of this regenerative response is stabilization of the actin (but not microtubule) cytoskeleton. We also demonstrate that this regenerative response may extend to other neurodegenerative diseases. Together, we provide evidence that activating dendrite regeneration pathways has the potential to slow-or even reverse-dendrite loss in neurodegenerative disease.

Background and purposeTraumatic brain injury (TBI) causes lifelong physical and psychological dysfunction in affected individuals. The current study investigated the effects of chronic nicotine exposure via E-cigarettes (E-cig) (vaping) on TBI-associated behavioural and biochemical changes.Experimental approachAdult C57/BL6J male mice were subjected to controlled cortical impact (CCI) followed by daily exposure to E-cig vapour for 6 weeks. Sensorimotor functions, locomotion, and sociability were subsequently evaluated by nesting, open field, and social approach tests, respectively. Immunoblots were conducted to examine the expression of mature brain-derived neurotrophic factor (mBDNF) and associated downstream proteins (p-Erk, p-Akt). Histological analyses were performed to evaluate neuronal survival and neuroinflammation.Key resultsPost-injury chronic nicotine exposure significantly improved nesting performance in CCI mice. Histological analysis revealed increased survival of cortical neurons in the perilesion cortex with chronic nicotine exposure. Immunoblots revealed that chronic nicotine exposure significantly up-regulated mBDNF, p-Erk and p-Akt expression in the perilesion cortex of CCI mice. Immunofluorescence microscopy indicated that elevated mBDNF and p-Akt expression were mainly localized within cortical neurons. Immunolabelling of Iba1 demonstrated that chronic nicotine exposure attenuated microglia-mediated neuroinflammation.Conclusions and implicationsPost-injury chronic nicotine exposure via vaping facilitates recovery of sensorimotor function by upregulating neuroprotective mBDNF/TrkB/Akt/Erk signalling. These findings suggest potential neuroprotective properties of nicotine despite its highly addictive nature. Thus, understanding the multifaceted effects of chronic nicotine exposure on TBI-associated symptoms is crucial for paving the way for informed and properly managed therapeutic interventions.

Photoreceptor degeneration is a major cause of untreatable blindness worldwide and has recently been targeted by emerging technologies, including cell- and gene-based therapies. Cell types of neural lineage have shown promise for replacing either photoreceptors or retinal pigment epithelial cells following delivery to the subretinal space, while cells of bone marrow lineage have been tested for retinal trophic effects following delivery to the vitreous cavity. Here we explore an alternate approach in which cells from the immature neural retinal are delivered to the vitreous cavity with the goal of providing trophic support for degenerating photoreceptors. Rat and human retinal progenitor cells were transplanted to the vitreous of rats with a well-studied photoreceptor dystrophy, resulting in substantial anatomical preservation and functional rescue of vision. This work provides scientific proof-of-principle for a novel therapeutic approach to photoreceptor degeneration that is currently being evaluated in clinical trials.

BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, there are limited data comparing the neuroprotective efficacy of diazepam versus midazolam following acute OP intoxication. To address this data gap, we used non-invasive imaging techniques to longitudinally quantify neuropathology in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) with and without post-exposure intervention with diazepam or midazolam. Magnetic resonance imaging (MRI) was used to monitor neuropathology and brain atrophy, while positron emission tomography (PET) with a radiotracer targeting translocator protein (TSPO) was utilized to assess neuroinflammation. Animals were scanned at 3, 7, 28, 65, 91, and 168 days post-DFP and imaging metrics were quantitated for the hippocampus, amygdala, piriform cortex, thalamus, cerebral cortex and lateral ventricles. In the DFP-intoxicated rat, neuroinflammation persisted for the duration of the study coincident with progressive atrophy and ongoing tissue remodeling. Benzodiazepines attenuated neuropathology in a region-dependent manner, but neither benzodiazepine was effective in attenuating long-term neuroinflammation as detected by TSPO PET. Diffusion MRI and TSPO PET metrics were highly correlated with seizure severity, and early MRI and PET metrics were positively correlated with long-term brain atrophy. Collectively, these results suggest that anti-seizure therapy alone is insufficient to prevent long-lasting neuroinflammation and tissue remodeling.

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

BACKGROUND: Although many molecules have been investigated as biomarkers for spinal cord injury (SCI) or ischemic stroke, none of them are specifically induced in central nervous system (CNS) neurons following injuries with low baseline expression. However, neuronal injury constitutes a major pathology associated with SCI or stroke and strongly correlates with neurological outcomes. Biomarkers characterized by low baseline expression and specific induction in neurons post-injury are likely to better correlate with injury severity and recovery, demonstrating higher sensitivity and specificity for CNS injuries compared to non-neuronal markers or pan-neuronal markers with constitutive expressions. METHODS: In animal studies, young adult wildtype and global Atf3 knockout mice underwent unilateral cervical 5 (C5) SCI or permanent distal middle cerebral artery occlusion (pMCAO). Gene expression was assessed using RNA-sequencing and qRT-PCR, while protein expression was detected through immunostaining. Serum ATF3 levels in animal models and clinical human samples were measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. RESULTS: Activating transcription factor 3 (ATF3), a molecular marker for injured dorsal root ganglion sensory neurons in the peripheral nervous system, was not expressed in spinal cord or cortex of naïve mice but was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI or ischemic stroke. Importantly, ATF3 protein levels in human serum were elevated in clinical patients within 24 hours after SCI or ischemic stroke. Moreover, Atf3 knockout mice, compared to the wildtype mice, exhibited worse neurological outcomes and larger damage regions after SCI or ischemic stroke, indicating that ATF3 has a neuroprotective function. CONCLUSIONS: ATF3 is an easily measurable, neuron-specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties. HIGHLIGHTS: ATF3 was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Serum ATF3 protein levels are elevated in clinical patients within 24 hours after SCI or ischemic stroke. ATF3 exhibits neuroprotective properties, as evidenced by the worse neurological outcomes and larger damage regions observed in Atf3 knockout mice compared to wildtype mice following SCI or ischemic stroke.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder that affects women of reproductive age, characterized by chronic anovulation, hyperandrogenism, and polycystic ovarian morphology. Emerging evidence indicates that neurological disorders play a significant role in the etiology of PCOS, highlighting the complex interplay between the central nervous system (CNS) and ovarian function. Yulinzhu, a traditional Chinese medicine (TCM) formulation, has been traditionally used to regulate menstrual cycles and improve fertility. This study aims to investigate the efficacy and mechanisms of Yulinzhu in treating PCOS induced by neurological disorders. METHODS: An extensive literature search was performed across electronic databases such as PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI), covering publications up to 1 June 2024. The review included randomized controlled trials (RCTs) that compared Yulin Zhu with placebo, standard care, or other active treatments in patients with PCOS. Two reviewers independently carried out data extraction and quality assessment. Meta-analyses were conducted using both fixed and random-effects models, with heterogeneity evaluated using the I2 statistic. RESULTS: We screened 891 records and included 6 studi es in the meta-analysis. The meta-analysis revealed that Yulinzhu about effective rate [RR = 1.19, 95% CI (1.10, 1.29), p < 0.0001], pregnancy rate [RR = 2.80, 95% CI (1.65, 4.76), p < 0.0001] and ovulation rate [RR = 1.33, 95% CI (1.10, 1.62), p = 0.04]. Meta-analysis shows the results of follicle estrogen [WMD = 0.69, 95% CI (-0.39, 1.78), p = 0.21], luteinizing hormone [WMD = -2.27, 95% CI (-3.86, -0.67), p = 0.005], testosterone [WMD = -0.44, 95% CI (-0.64, -0.25), p < 0.0001], estradiol [WMD = 16.20, 95% CI (2.74, 29.67), p < 0.0001]. CONCLUSION: This study demonstrates that plant medicine compund Yulinzhu may effectively treats PCOS including hormonal regulation, anti-inflammatory actions, and neuroprotection. We expect further research with larger, well-designed clinical trials to substantiate our conclusions.

BACKGROUND: DATATOP was a study of early Parkinsons disease (PD) conducted in the 1980 s, before mandatory folic acid fortification in the United States. Our analysis of its baseline serum samples revealed a geometric mean vitamin B12 of 369 pg/mL and homocysteine (tHcy) of 9.5μmol/l. We also found that low B12 predicted greater worsening of ambulatory capacity (AC) and elevated tHcy (>15μmol/L) predicted greater declines in cognitive function. OBJECTIVE: We sought to measure B12 and tHcy in contemporary trial participants with early PD who had not started dopaminergic treatment and to determine whether these analytes were associated with clinical progression. METHODS: We measured B12 and tHcy from baseline and end-of-study blood samples from three recent clinical trials. RESULTS: Baseline geometric mean B12 levels for these studies ranged from 484- 618 pg/ml and for tHcy ranged from 7.4- 10μmol/L. Use of B12-containing supplements ranged from 41- 61%, and those taking supplements had higher B12 and lower tHcy. Those who began levodopa, but were not taking B12-supplements, had greater end-of-study tHcy. There was no association of baseline tHcy > 15μmol/L with annualized change in Montreal Cognitive Assessment and no association of baseline B12 tertiles with change in AC. CONCLUSIONS: In these longitudinal trials, B12 levels were higher than for DATATOP, due in large part to increased B12-supplement intake, while tHcy levels were similar. Initiation of levodopa was associated with increases of tHcy in those not taking a B12-containing supplement. These smaller studies did not replicate prior findings of low B12 and elevated tHcy with features of progression, possibly due to higher baseline B12.

BackgroundInfection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts in neurons that can have devastating consequences in the immunocompromised. In the immunocompetent individual, anti-parasitic effector mechanisms and a balanced immune response characterized by pro- and anti-inflammatory cytokine production establishes an asymptomatic infection that rarely leads to neurological symptoms. Several mechanisms are known to play a role in this successful immune response in the brain including T cell production of IFNγ and IL-10 and the involvement of CNS resident cells. This limitation of clinical neuropathology during chronic infection suggests a balance between immune response and neuroprotective mechanisms that collectively prevent clinical manifestations of disease. However, how these two vital mechanisms of protection interact during chronic Toxoplasma infection remains poorly understood.Main textThis study demonstrates a previously undescribed connection between innate neutrophils found chronically in the brain, termed "chronic brain neutrophils" (CBNeuts), and neuroprotective mechanisms during Toxoplasma infection. Lack of CBNeuts during chronic infection, accomplished via systemic neutrophil depletion, led to enhanced infection and deleterious effects on neuronal regeneration and repair mechanisms in the brain. Phenotypic and transcriptomic analysis of CBNeuts identified them as distinct from peripheral neutrophils and revealed two main subsets of CBNeuts that display heterogeneity towards both classical effector and neuroprotective functions in an age-dependent manner. Further phenotypic profiling defined expression of the neuroprotective molecules NRG-1 andErbB4 by these cells, and the importance of this signaling pathway during chronic infection was demonstrated via NRG-1 treatment studies.ConclusionsIn conclusion, this work identifies CBNeuts as a heterogenous population geared towards both classical immune responses and neuroprotection during chronic Toxoplasma infection and provides the foundation for future mechanistic studies of these cells.

In 2011, the UK medical research charity Cure Parkinsons set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinsons disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.

PURPOSE: The aim of this study was to investigate, the neuroprotective effects of a new Gramine derivative named: ITH12657, in a model of retinal excitotoxicity induced by intravitreal injection of NMDA. METHODS: Adult Sprague Dawley rats received an intravitreal injection of 100 mM NMDA in their left eye and were treated daily with subcutaneous injections of ITH12657 or vehicle. The best dose-response, therapeutic window study, and optimal treatment duration of ITH12657 were studied. Based on the best survival of Brn3a + RGCs obtained from the above-mentioned studies, the protective effects of ITH12657 were studied in vivo (retinal thickness and full-field Electroretinography), and ex vivo by quantifying the surviving population of Brn3a + RGCs, αRGCs and their subtypes α-ONsRGCs, α-ONtRGCs, and α-OFFRGCs. RESULTS: Administration of 10 mg/kg ITH12657, starting 12 h before NMDA injection and dispensed for 3 days, resulted in the best significant protection of Brn3a + RGCs against NMDA-induced excitotoxicity. In vivo, ITH12657-treated rats showed significant preservation of retinal thickness and functional protection against NMDA-induced retinal excitotoxicity. Ex vivo results showed that ITH12657 afforded a significant protection against NMDA-induced excitotoxicity for the populations of Brn3a + RGC, αRGC, and αONs-RGC, but not for the population of αOFF-RGC, while the population of α-ONtRGC was fully resistant to NMDA-induced excitotoxicity. CONCLUSION: Subcutaneous administration of ITH12657 at 10 mg/kg, initiated 12 h before NMDA-induced retinal injury and continued for 3 days, resulted in the best protection of Brn3a + RGCs, αRGC, and αONs-RGC against excitotoxicity-induced RGC death. The population of αOFF-RGCs was extremely sensitive while α-ONtRGCs were fully resistant to NMDA-induced excitotoxicity.

ObjectiveMethamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders.Method423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M-/M+) and/or cannabis (C-/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition.ResultsGlobally, M+C+ performed worse than M-C- but better than M+C-. M+C+ outperformed M+C- on measures of verbal fluency, information processing speed, learning, memory, and working memory. M-C+ did not display lower performance than M-C- globally or on any domain measures, and M-C+ even performed better than M-C- on measures of learning, memory, and working memory.ConclusionsOur findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.

Background: Microbial melanins possess a broad spectrum of biological activities. However, there is little understanding of their neuroprotective and neuronal cell differentiation properties. This study aimed to extract, purify, and modify melanins from two medicinal fungi (Daedaleopsis tricolor and Fomes fomentarius), and to evaluate their antioxidant activity, as well as their cell protective ability against neurotoxins. In addition, the study also investigated the feasibility of combining melanins or modified melanins with retinoic acid (RA) to induce neuronal differentiation. Methods: Melanin was extracted and purified using alkaline acid-based methods. Antioxidant activities and neuroprotective effects were evaluated using the DPPH (1,1-diphenyl-2-picrylhydrazyl) and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assays, respectively. In addition, morphological changes of SH-SY5Y cells were recorded by using a Pannoramic MIDI scanner. Results: All melanins and arginine-modified melanins displayed mild DPPH scavenging activities, which were statistically lower than that of ascorbic acid (p < 0.05). In terms of neuroprotection, both melanins and arginine-modified melanins exhibited significant cell protection against H2O2 after 24 h exposure (p < 0.05). Notably, there is no significant difference between F. fomentarius melanin and its modified form as they both increased cell viability by about 20%. Contrarily, while D. tricolor melanin enhanced the cell viability with 16%, its modified form increased the cell viability with 21%. These activities, however, are significantly lower than the positive control (N-acetylcysteine, p < 0.05). Regarding MPTP, only the arginine-modified melanins of the two fungi significantly protected the cells after 24 h exposure to the toxin (p < 0.05). Specifically, F. fomentarius and D. tricolor modified melanins enhanced the cell viability with 10.2% and 11.1%, respectively, whereas that of the positive control was 13.2%. Interestingly, combining RA (10 µM) with 20 µg/mL of either F. fomentarius, or especially D. tricolor arginine-modified melanin, significantly promoted neuroblastoma cell differentiation into mature neuronal cells compared to using RA alone (p < 0.05). Conclusions: The arginine-modified melanins of D. tricolor and F. fomentarius have potential for neuroprotection against Parkinsonian neurotoxins. In addition, the arginine-modified melanin of D. tricolor may serve as an excellent material for research in neuroblastoma treatment. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) results from various causes, including sports‐related incidents, degenerative cervical myelopathy, traffic accidents, and falls. SCI typically leads to sensory and motor dysfunction and even paralysis. Current treatments for SCI include systemic administration of high‐dose steroids and surgical decompression and stabilization. However, excessive use of glucocorticoids may increase susceptibility to infections and systemic bleeding. The long‐term effect of surgery intervention remains unclear, with ongoing debates regarding its timing, efficacy, and safety. Therefore, innovative approaches are urgently needed to alleviate secondary injuries and promote spinal recovery. One emerging therapeutic approach for SCI is modulating the microenvironments to achieve neuroprotection and neurogenesis during recovery. Several biomaterials with favorable physicochemical properties have been developed to enhance therapeutic effects by regulating microenvironments. This Review first discusses the pathology of SCI microenvironments and then introduces biomaterials‐based regulatory strategies targeting various microenvironmental components, including anti‐inflammation, anti‐oxidation, reduction of excitotoxicity, revascularization, neurogenesis, and scar density reduction. Additionally, the research and clinical application prospects for microenvironment regulation are presented. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark (MP) mouse model of PD recapitulates several facets of Parkinson's disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress. Thus, we hypothesized that administration of a ketone ester–enriched diet (KEED) would improve motor and dopamine release deficits in MP mice. Motor function (rotarod and open field tests), dopamine release (fast‐scan cyclic voltammetry), tissue dopamine levels (gas chromatography–mass spectrometry) and dopamine neurons and axons (immunofluorescence) were assessed in MP, and control mice fed either the standard or a KEED. When started on the ketone diet before motor dysfunction onset, MP mice had improved motor function relative to standard diet (SD) MP mice. While the KEED did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MP mice was greater than SD MP mice but less than control mice. In a follow‐up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MP mice relative to SD MP mice. The improvement in motor dysfunction indicates that a KEED or ketone supplement may have a beneficial effect on delaying motor deficit progression in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: Riluzole exhibits neuroprotective and therapeutic effects in several neurological disease models associated with excessive synaptic glutamate (Glu) release. We recently showed riluzole prevents acute excitotoxic hippocampal neural injury at 3 days in the kainic acid (KA) model of temporal lobe epilepsy (TLE). Currently, it is unknown if preventing acute neural injury and the neuroinflammatory response is sufficient to suppress epileptogenesis. Methods: The KA rat model of TLE was used to determine if riluzole attenuates acute hippocampal neural injury and reactive gliosis. KA was administered to adult male Sprague-Dawley (250 g) rats at 5 mg/kg/hr until status epilepticus (SE) was observed, and riluzole was administered at 10 mg/kg 1 h and 4 h after SE and once per day for the next 2 days. Immunostaining was used to assess neural injury (FJC and NeuN), microglial activation (Iba1 and ED-1/CD68) and astrogliosis (GFAP and vimentin) at day 7 and day 14 after KA-induced SE. Learning and memory tests (Y-maze, Novel object recognition test, Barnes maze), behavioral hyperexcitability tests, and spontaneous generalized recurrent seizure (SRS) activity (24-hour video monitoring) were assessed at 11–15 weeks. Results: Here we show that KA-induced hippocampal neural injury precedes the neuroimmune response and that riluzole attenuates acute neural injury, microglial activation, and astrogliosis at 7 and 14 days. We find that reducing acute hippocampal injury and the associated neuroimmune response following KA-induced SE by riluzole attenuates hippocampal-dependent cognitive impairment, behavioral hyperexcitability, and tonic/clonic generalized SRS activity after 3 months. We also show that riluzole attenuates SE-associated body weight loss during the first week after KA-induced SE. Discussion: Riluzole acts on multiple targets that are involved to prevent excessive synaptic Glu transmission and excitotoxic neuronal injury. Attenuating KA-induced neural injury and subsequent microglia/astrocyte activation in the hippocampus and extralimbic regions with riluzole reduces TLE-associated cognitive deficits and generalized SRS and suggests that riluzole could be a potential antiepileptogenic drug. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD) are common complications of diabetes, arising from insulin resistance, inflammation, and other pathological processes in the central nervous system. The potential of numerous antidiabetic agents to modify neurodegenerative disease progression, both preclinically and clinically, has been assessed. These agents may provide additional therapeutic benefits beyond glycemic control. Introduced in the twenty-first century, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of antidiabetic drugs noted not only for their potent glucose-lowering effects but also for their cardiovascular and renal protective benefits. Various GLP-1RAs have been demonstrated to have significant benefits in in vitro and in vivo models of neurodegenerative diseases through modulating a variety of pathogenic mechanisms, including neuroinflammation, autophagy, mitochondrial dysfunction, and the abnormal phosphorylation of pathognomonic proteins. These agents also have substantial protective effects on cognitive and behavioral functions, such as motor function. However, clinical trials investigating GLP-1RAs in diseases such as AD, PD, mild cognitive impairment, psychiatric disorders, and diabetes have yielded mixed results for cognitive and motor function. This review examines the link between diabetes and neurodegenerative diseases, explores the effects of antidiabetic agents on neurodegeneration, provides a concise overview of the GLP-1 pathway, and discusses both preclinical and clinical trial outcomes of GLP-1RAs for neurodegenerative diseases, including their effects on cognition in AD and PD. This review also proposed new strategies for the design of future clinical trials on GLP-1 RAs for both AD and PD. [ABSTRACT FROM AUTHOR]

Isoalantolactone (ISA) is a sesquiterpene lactone that could be isolated from Inula helenium as well as many other herbal plants belonging to Asteraceae. Over the past 2 decades, lots of researches have been made on ISA, which owns multiple pharmacological effects, such as antimicrobial, anticancer, anti-inflammatory, neuroprotective, antidepressant-like activity, as well as others. The anticancer effects of ISA involve proliferation inhibition, ROS overproduction, apoptosis induction and cell cycle arrest. Through inhibiting NF-κB signaling, ISA exerts its anti-inflammatory effects which are involved in the neuroprotection of ISA. This review hackled the reported pharmacological effects of ISA and associated mechanisms, providing an update on understanding its potential in drug development. [ABSTRACT FROM AUTHOR]

Introduction: Traditional Chinese medicine Gastrodia elata Blume (GEB) possesses properties that soothe the liver and dispel wind. Its constituents exhibit numerous pharmacological properties, including neuroprotective effects, analgesic properties for headache relief, memory enhancement, and others. Borneol enhances drug absorption by traversing the blood-brain barrier, thereby improving its bioavailability and therapeutic efficacy. The research aimed to design innovative drug molecules and contribute to the beneficial exploration of compound Chinese medicine modernization. Methods: This study employed the strategy of "compound Chinese medicine molecular chemistry" to integrate and fuse the effective substances of compound Chinese medicines. An excitotoxic injury model was established by exposing PC12 cells to glutamate. Cell viability was quantitatively evaluated utilizing a colorimetric assay with the CCK-8 reagent kit. Genecards, Disgenet, and OMIM databases were used to identify potential disease-related targets. Molecular docking methods were performed to predict the binding interactions between compounds and core targets. Results: We designed and synthesized compounds TB-1 to TB-16. Following the evaluation of their safety, TB-1, TB-2, TB-12, and TB-16 were selected for further investigation of their neuroprotective properties. The compound designed in this study exhibits a dose-dependent protective effect on glutamate-damaged PC12 cells. Further network pharmacology and molecular docking analyses indicate that TB-2 possesses a potential therapeutic effect against cerebral ischemia, and its possible targets were SRC, MAPK1 and KDR. Discussion: The results indicated that TB-2 displayed a significant neuroprotective effect against Glu-induced injury in PC12 cells, suggesting potential therapeutic implications for cerebral ischemia. [ABSTRACT FROM AUTHOR]

Purpose: Glaucoma is a leading cause of irreversible blindness. Glaucomatous intraocular pressure (IOP) triggers deleterious effects, including gliosis, optic nerve (ON) axonal retraction, neurotrophic factor deprivation, inflammation, and other pathological events, leading to retinal ganglion cell (RGC) loss. Trophic factor impairment enhances RGC apoptosis susceptibility. Neuritin 1 (NRN1), a neurotrophic protein downstream of various neurotrophins, exhibited RGC protection and regeneration in axotomy models. We evaluated human recombinant NRN1's impact on human RGCs cultured in pressurized conditions within the ex vivo translaminar autonomous system to simulate glaucoma pathogenesis. Methods: Human glaucomatous and non-glaucomatous donor eyes were obtained from eye banks according to the Declaration of Helsinki. Initially, we evaluated NRN1and RGC marker expression in glaucoma and non-glaucomatous retina to determine the NRN1 level and its association with RGC loss. Further, we evaluated NRN1's therapeutic potential by treating pressurized human eyes at normal and high IOP for seven days. Retina, ON, and conditioned medium were analyzed for RGC survival (THY1, RBPMS), gliosis (GFAP), apoptosis (CASP3, CASP7), and extracellular matrix deposition (COLIV, FN) by qRT-PCR and western blotting. Paraphenylenediamine staining assessed ON axonal degeneration, whereas ex vivo electroretinogram assessed retinal activity. Results: Glaucomatous retinas exhibited significant reductions in both NRN1 (*p = 0.007, n = 5) and RGC marker expression (*p = 0.04, n = 5). NRN1 treatment reduced gliosis, extracellular matrix deposition, ON degeneration, and increased retinal activity in pressure-perfused eyes. Conclusions: Our study confirms that NRN1 enhances human RGC survival and improves retinal function in degenerative conditions, substantiating it as a promising candidate for rescuing human RGCs from degeneration. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by cognitive decline and the accumulation of amyloid-beta plaques and hyperphosphorylated tau protein. The role of tau lactylation at the K677 site in AD progression is not well understood. This study explores how tau K677 lactylation affects ferritinophagy, ferroptosis, and their functions in an AD mouse model. Results show that mutating the K677 site to R reduces tau lactylation and inhibits ferroptosis by regulating iron metabolism factors like NCOA4 and FTH1.Tau-mutant mice showed improved memory and learning skills compared to wild-type mice. The mutation also reduced neuronal damage and was associated with decreased tau lactylation at the K677 site, regardless of phosphorylated tau levels. Gene set enrichment analysis showed that lactylation at this site was linked to the MAPK pathway, which was important for ferritinophagy in AD mice. In summary, our research indicates that the K677 mutation in tau protein may protect against AD by influencing ferritinophagy and ferroptosis through MAPK signaling pathways. Understanding these modifications in tau could lead to new treatments for AD. [Display omitted] • The K677 mutation in the tau protein may confer a protective effect against Alzheimer's disease. • The results show that replacing the K677 residue with arginine reduces tau lactylation and inhibits ferroptosis. • Decreased neuronal damage was linked to reduced tau lactylation at K677, independent of phosphorylated tau levels. [ABSTRACT FROM AUTHOR]

Neuroinflammation that is caused by microglia, the main immune cells of the brain, contributes to neurodegenerative diseases. Psychedelics, including psilocybin and lysergic acid diethylamide (LSD), possess certain anti-inflammatory properties and, therefore, should be considered as drug candidates for treating neuroinflammatory pathologies. When ingested, psilocybin is rapidly dephosphorylated to yield psilocin, which crosses the blood–brain barrier and exerts psychotropic activity by interacting with the 5-hydroxytryptamine 2A receptors (5-HT2ARs) on neurons. Since microglia express all three 5-HT2R isoforms, we hypothesized that, by interacting with these receptors, psilocin beneficially modulates select neuroimmune functions of microglia. We used microglia-like cell lines to demonstrate that psilocin, at non-toxic concentrations, did not affect the secretion of tumor necrosis factor (TNF) by immune-stimulated microglial cells, but significantly inhibited their phagocytic activity, the release of reactive oxygen species (ROS), and nitric oxide (NO) production. The inhibitory activity of psilocin on the latter two functions was similar to that of two selective 5-HT2R agonists, namely, 25I-NBOH and Ro60-0175. The role of this subfamily of receptors was further demonstrated by the application of 5-HT2R antagonists cyproheptadine and risperidone. Psilocin should be considered a novel drug candidate that might be effective in treating neuroimmune disorders, such as neurodegenerative diseases, where reactive microglia are significant contributors. [ABSTRACT FROM AUTHOR]

Caloric restriction (CR) has been proposed as a nutritional strategy to combat chronic diseases, including neurodegenerative diseases, as well as to delay aging. However, despite the benefits of CR, questions remain about its underlying mechanisms and cellular and molecular targets. Objective: As inflammatory processes are the basis or accompany chronic diseases and aging, we investigated the protective role of CR in the event of an acute inflammatory stimulus. Methods: Peripheral inflammatory and metabolic parameters were evaluated in Wistar rats following CR and/or acute lipopolysaccharide (LPS) administration, as well as glial changes (microglia and astrocytes), in two regions of the brain (hippocampus and hypothalamus) involved in the inflammatory response. We used a protocol of 30% CR, for 4 or 8 weeks. Serum and brain parameters were analyzed by biochemical or immunological assays. Results: Benefits of CR were observed during the inflammatory challenge, where the partial reduction of serum interleukin-6, mediated by CR, attenuated the systemic response. In the central nervous system (CNS), specifically in the hippocampus, CR attenuated the response to the LPS, as evaluated by tumor necrosis factor alpha (TNFα) levels. Furthermore, in the hippocampus, CR increased the glutathione (GSH) levels, resulting in a better antioxidant response. Discussion: This study contributes to the understanding of the effects of CR, particularly in the CNS, and expands knowledge about glial cells, emphasizing their importance in neuroprotection strategies. [ABSTRACT FROM AUTHOR]

Slowing or halting progression continues to be a major unmet medical need in Parkinson's disease (PD). Numerous trials over the past decades have tested a broad range of interventions without ultimate success. There are many potential reasons for this failure and much debate has focused on the need to test 'disease-modifying' candidate drugs in the earliest stages of disease. While generally accepted as a rational approach, it is also associated with significant challenges around the selection of trial populations as well as trial outcomes and durations. From a health care perspective, intervening even earlier and before at-risk subjects have gone on to develop overt clinical disease is at the heart of preventive medicine. Recent attempts to develop a framework for a biological definition of PD are aiming to enable 'preclinical' and subtype-specific diagnostic approaches. The present review addresses past efforts towards disease-modification, including drug targets and reasons for failure, as well as novel targets that are currently being explored in disease-modification trials in early established PD. The new biological definitions of PD may offer new opportunities to intervene even earlier. We critically discuss the potential and challenges around planning 'disease-prevention' trials in subjects with biologically defined 'preclinical' or prodromal PD. [ABSTRACT FROM AUTHOR]

Thoracic spinal cord injury (SCI) profoundly impairs motor and sensory functions, significantly reducing life quality without currently available effective treatments for neuroprotection or full functional regeneration. This study investigated the neurotrophic and synaptic recovery potential of gonadotropin-releasing hormone (GnRH) and growth hormone (GH) treatments in ovariectomized rats subjected to thoracic SCI. Employing a multidisciplinary approach, we evaluated the effects of these hormones upon gene expression of classical neurotrophins (NGF, BDNF, and NT3) as well as indicative markers of synaptic function (Nlgn1, Nxn1, SNAP25, SYP, and syntaxin-1), together with morphological assessments of myelin sheath integrity (Klüver-Barrera staining and MBP immunoreactivity) and synaptogenic proteins (PSD95, SYP) by immunohystochemistry (IHC) , and also on the neuromotor functional recovery of hindlimbs in the lesioned animals. Results demonstrated that chronic administration of GnRH and GH induced notable upregulation in the expression of several neurotrophic and synaptogenic activity genes. Additionally, the treatment showed a significant impact on the restoration of functional synaptic markers and myelin integrity. Intriguingly, while individual GnRH application induced certain recovery benefits, the combined treatment with GH appeared to inhibit neuromotor recovery, suggesting a complex interplay in hormonal regulation post-SCI. GnRH and GH are bioactive and participate in modulating neurotrophic responses and synaptic restoration under neural damage conditions, offering insights into novel therapeutic approaches for SCI. However, the intricate effects of combined hormonal treatment accentuate the necessity for further investigation that conduce to optimal and novel therapeutic strategies for patients with spinal cord lesions. [ABSTRACT FROM AUTHOR]

Introduction: This work aims to determine the effect on nerve fiber layer (NFL) and ganglion cell complex (GCC) thickness trends in eyes with open-angle glaucoma (OAG) treated with Vision Protection Therapy™ (VPT). Methods: A retrospective analysis of spectral-domain optical coherence tomography (OCT) measured NFL and GCC thickness trends was performed, excluding eyes with poor-quality scans and principal diagnoses other than OAG. This study compares eyes with OAG managed conventionally with IOP control alone (controls) to eyes managed with the addition of VPT (VPT eyes). The direction (+ or −) and magnitude (microns/year) of the OCT trends were the study endpoints. Results: Seventy-eight control eyes of 40 patients and 61 VPT-treated eyes of 39 patients were included in the study. Positive NFL trends were noted in 5% of control eyes vs. 71% of VPT eyes (p < 0.0001). Positive GCC trends were noted in 8% of control eyes vs. 43% of VPT eyes (p < 0.0001). Mean NFL trends (µm/year) were − 0.692 for controls vs. 0.347 for VPT (p < 0.0001). Mean GCC trends (µm/year) were − 0.554 for controls vs. − 0.148 for VPT (p = 0.0175). Conclusions: The addition of VPT to the conventional management of OAG resulted in highly significant improvements in NFL and GCC trends, indicating a reversal of key indicators of glaucoma severity and progression. [ABSTRACT FROM AUTHOR]

Ginsenosides are the primary component discernible from ginseng, including Rb1, Rb2, Rd, Rg1, Rg2, and compound K, and so forth. They have been shown to have multiple pharmacological activities. In recent years, more and more studies have been devoted to the neuroprotection of various ginsenosides against neurological diseases and their potential mechanisms. This paper comprehensively summarizes and reviews the neuroprotective effects of various ginsenosides on neurological diseases, especially acute and chronic neurodegenerative diseases, and their mechanisms, as well as their potential therapeutic applications to promote neuroprotection in disease prevention, treatment, and prognosis. Briefly, ginsenosides exert effective neuroprotective effects on neurological conditions, including stroke, Alzheimer's disease, Parkinson's disease, and brain/spinal cord injuries through a variety of molecular mechanisms, including anti‐inflammatory, antioxidant, and anti‐apoptotic. Among them, some signaling pathways play important roles in related processes, such as PI3K/Akt, TLR4/NF‐κB, ROS/TXNIP/NLRP3, HO‐1/Nrf2, Wnt/β‐catenin, and Ca2+ pathway. In conclusion, the present study reviews the research progress on the neuroprotective effects of ginsenosides in the last decade, with the aim of furnishing essential theoretical underpinning and effective references for further research and exploration of the multiple medicinal values of Chinese herbal medicines and their small molecule compounds, including ginseng and panax ginseng. Because there is less evidence in the existing clinical studies, future research should be focused on clinical trials in order to truly reflect the clinical value of various ginsenosides for the benefit of patients. [ABSTRACT FROM AUTHOR]

Background: Phytocannabinoids inhibit the aggregation and neurotoxicity of the neurotoxic Alzheimer's disease protein β amyloid (Aβ). We characterised the capacity of five proprietary medical cannabis extracts, heated and non‐heated, with varying ratios of cannabidiol and Δ9‐tetrahydrocannabinol and their parent carboxylated compounds to protect against lipid peroxidation and Aβ‐evoked neurotoxicity in PC12 cells. Methods: Neuroprotection against lipid peroxidation and Aβ1–42‐induced cytotoxicity was assessed using the thiazolyl blue tetrazolium bromide (MTT) assay. Transmission electron microscopy was used to visualise phytocannabinoid effects on Aβ1–42 aggregation and fluorescence microscopy. Results: Tetrahydrocannabinol (THC)/tetrahydrocannabinolic acid (THCA)‐predominant cannabis extracts demonstrated the most significant overall neuroprotection against Aβ1–42‐induced loss of PC12 cell viability. These protective effects were still significant after heating of extracts, while none of the extracts provided significant neuroprotection to lipid peroxidation via tbhp exposure. Modest inhibition of Aβ1–42 aggregation was demonstrated only with the non‐heated BC‐401 cannabis extract, but overall, there was no clear correlation between effects on fibrils and conferral of neuroprotection. Conclusions: These findings highlight the variable neuroprotective activity of cannabis extracts containing major phytocannabinoids THC/THCA and cannabidiol (CBD)/cannabidiolic acid (CBDA) on Aβ‐evoked neurotoxicity and inhibition of amyloid β aggregation. This may inform the future use of medicinal cannabis formulations in the treatment of Alzheimer's disease and dementia. [ABSTRACT FROM AUTHOR]

Precise control of norepinephrine (NE) levels and NE-receptor interaction is crucial for proper function of the brain. Much evidence for this view comes from experimental studies that indicate an important role for NE in the pathophysiology and treatment of various conditions, including cognitive dysfunction, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and sleep disorders. NE provides neuroprotection against several types of insults in multiple ways. It abrogates oxidative stress, attenuates neuroinflammatory responses in neurons and glial cells, reduces neuronal and glial cell activity, promotes autophagy, and ameliorates apoptotic responses to a variety of insults. It is beneficial for the treatment of neurodegenerative diseases because it improves the generation of neurotrophic factors, promotes neuronal survival, and plays an important role in the regulation of adult neurogenesis. This review aims to present the evidence supporting a principal role for NE in neuroprotection, and molecular mechanisms of neuroprotection. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is a common therapy for managing Parkinson's disease (PD) in clinical practice. However, a complete understanding of its mode of action is still needed. DBS is believed to work primarily through electrical and neurochemical pathways. Furthermore, DBS has other mechanisms of action. This review explores the fundamental concepts and applications of DBS in treating PD, including its mechanisms, clinical implications, and recent research. [ABSTRACT FROM AUTHOR]

Objective: Previously, we have successfully purified and synthesized viscolin, an agent derived from Viscum coloratum extract, which has shown significant potential in the treatment of stroke. Our study aimed to evaluate the neuroprotective effects of viscolin. Methods: We first assessed the cytotoxicity of viscolin on primary neuronal cultures and determined its antioxidant and radical scavenging properties. Subsequently, we identified the optimal dose-response of viscolin in protecting against glutamate-induced neurotoxicity. Results: Our results demonstrated that viscolin at a concentration of 10 μM effectively reduced neuronal cell death up to 6 hours after glutamate-induced neurotoxicity. Additionally, we investigated the therapeutic window of opportunity and the potential of viscolin in preventing necrotic and apoptotic damage in cultured neurons exposed to oxygen glucose deprivation-induced neurotoxicity. Our findings showed that viscolin treatment significantly reduced DNA breakage, prevented the release of cytochrome c from mitochondria to cytosol, increased the expression of anti-apoptotic protein Bcl-2, decreased the expression of pro-apoptotic protein Bax, and reduced the number of TUNEL-positive cells. Additionally, our in vivo investigation demonstrated a reduction in brain infarction following middle cerebral artery occlusion. Conclusion: Viscolin has potential utility as a therapeutic agent in the treatment of stroke. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors, leading to progressive photoreceptor loss. Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival. This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation (tcES) in mice affected by inherited retinal degeneration. Additionally, the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans. In this study, we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular, sine, and ramp waveforms. To investigate the functional effects of electrical stimulation on photoreceptors, we used human retinal explant cultures and rhodopsin knockout (Rho–/–) mice, demonstrating progressive photoreceptor degeneration with age. Human retinal explants isolated from the donors' eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro. Photoreceptor density was evaluated by rhodopsin immunolabeling. In vivo Rho–/– mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms. Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response (OMR), respectively. Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas. Oscilloscope recordings indicated effective delivery of rectangular, sine, and ramp waveforms to the retina by transcorneal electrical stimulation, of which the ramp waveform required the lowest voltage. Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes. The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro (~0.5–1.5°C). Electrical stimulation increased photoreceptor survival in human retinal explant cultures, particularly at the ramp waveform. Transcorneal electrical stimulation (rectangular + ramp) waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results. Histology and immunolabeling demonstrated increased photoreceptor survival, improved outer nuclear layer thickness, and increased bipolar cell sprouting in Rho–/– mice. These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina, improves photoreceptor survival in both human and mouse retinas, and increases visual function in Rho–/– mice. Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion. [ABSTRACT FROM AUTHOR]

H2O2 is a significant reactive oxygen species (ROS) that hinders redox‐mediated processes and contributes to oxidative stress and neurodegenerative disorders. Oxidative stress causes impairment of cell macromolecules, which results in cell dysfunction and neurodegeneration. Alzheimer's disease and other neurodegenerative diseases are serious conditions linked to oxidative stress. Antioxidant treatment approaches are a novel and successful strategy for decreasing neurodegeneration and reducing oxidative stress. This study explored the antioxidant and neuroprotective characteristics of KK14 peptide synthesized from LEAP 2B (liver‐expressed antimicrobial peptide‐2B) derived from Cyprinus carpio L. Molecular docking studies were used to assess the antioxidant properties of KK14. The peptide at concentrations 5–45 μM was examined by using in vitro and in vivo assessment. Analysis was done on the developmental and neuroprotective potential of KK14 peptide treatment in H2O2‐exposed zebrafish larvae which showed Nonlethal deformities. KK14 improves antioxidant enzyme activity like catalase and superoxide dismutase. Furthermore, it reduces neuronal damage by lowering lipid peroxidation and nitric oxide generation while increasing acetylcholinesterase activity. It improved the changes in swimming behavior and the cognitive damage produced by exposure to H2O2. To further substantiate the neuroprotective potential of KK14, intracellular ROS levels in zebrafish larvae were assessed. This led to a reduction in ROS levels and diminished lipid peroxidation. The KK14 has upregulated the antioxidant genes against oxidative stress. Overall, this study proved the strong antioxidant activity of KK14, suggesting its potential as a strong therapeutic option for neurological disorders caused by oxidative stress. Highlights: KK14, a short‐chain sequence of amino acids derived from Cyprinus carpio, has a protective effect against free radicals.In H2O2‐exposed zebrafish larvae, KK14 reduced intracellular ROS and lipid peroxidation.Zebrafish model showed increased SOD, catalase, and glutathione activities.The KK14 revealed improved cognitive behavior and thus exhibited neuroprotective effects.The novel peptide KK14, a putative antioxidant peptide, has a significant and promising role in therapeutic drug discovery. Structural and Functional Insights into KK14 Peptide from Cyprinus carpio: Bioinformatics Analysis of its Toxicological, Neurobehavioral, and Antioxidant Properties [ABSTRACT FROM AUTHOR]

Lessertia frutescens (synonym Sutherlandia frutescens) is an important South African medicinal plant used traditionally to treat different human pathologies and is considered an adaptogenic plant. This study sought to isolate compounds from the plant and determine their protective potentials using SH-SY5Y cells and MPP+ (1-methyl-4-phenylpyridinium) to mimic Parkinson's disease. The phytochemical analysis of a 70% aqueous methanolic extract of L. frutescens leaves resulted in the isolation and identification of 11 pure compounds (1–11), among which compounds 1 and 2 were identified as new metabolites. The new compounds were characterised using IR, UV, NMR, and HRESIMS and were given the trivial names lessertiosides A (1) and B (2). Additionally, the flavonoids 8-methoxyvestitol (7) and mucronulatol (8) were isolated for the first time from the plant. The biological actions show that the isolated compounds had negligible toxicity on SH-SY5Y cells and improved cell viability in the cells exposed to MPP+. Furthermore, as a mechanism of action, the compounds could sustain cellular ATP generation and prevent MPP+-induced apoptotic cell death. Our findings provide evidence for the neuroprotective properties of compounds isolated from L. frutescens in MPP+-induced neuronal damage for the first time and create an avenue for these compounds to be further investigated to elucidate their molecular targets. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) constitutes a significant clinical challenge, and there is extensive research focused on identifying molecular activities that can facilitate the repair of spinal cord injuries. Mammalian sterile 20-like kinase 2 (MST2), a core component of the Hippo signaling pathway, plays a key role in apoptosis and cell growth. However, its role in neurite outgrowth after spinal cord injury remains unknown. Through comprehensive in vitro and in vivo experiments, we demonstrated that MST2, predominantly expressed in neurons, actively participated in the natural development of the CNS. Post-SCI, MST2 expression significantly increased, indicating its activation and potential role in the early stages of neural recovery. Detailed analyses showed that MST2 knockdown impaired neurite outgrowth and motor function recovery, whereas MST2 overexpression led to the opposite effects, underscoring MST2's neuroprotective role in enhancing neural repair. Further, we elucidated the mechanism underlying MST2's action, revealing its interaction with AKT and positive regulation of AKT activity, a well-established promoter of neurite outgrowth. Notably, MST2's promotion of neurite outgrowth and motor functional recovery was diminished by AKT inhibitors, highlighting the dependency of MST2's neuroprotective effects on AKT signaling. In conclusion, our findings affirmed MST2's pivotal role in fostering neuronal neurite outgrowth and facilitating functional recovery after SCI, mediated through its positive modulation of AKT activity. In conclusion, our findings confirmed MST2's crucial role in neural protection, promoting neurite outgrowth and functional recovery after SCI through positive AKT activity modulation. These results position MST2 as a potential therapeutic target for SCI, offering new insights into strategies for enhancing neuroregeneration and functional restoration. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most common neurological disorders in the world. Common epileptic drugs generally affect ion channels or neurotransmitters and prevent the emergence of seizures. However, up to a third of the patients suffer from drug-resistant epilepsy, and there is an urgent need to develop new therapeutic strategies that go beyond acute antiepileptic (antiseizure) therapies towards therapeutics that also might have effects on chronic epilepsy comorbidities such as cognitive decline and depression. The mitochondrial calcium uniporter (MCU) mediates rapid mitochondrial Ca2+ transport through the inner mitochondrial membrane. Ca2+ influx is essential for mitochondrial functions, but longer elevations of intracellular Ca2+ levels are closely associated with seizure-induced neuronal damage, which are underlying mechanisms of cognitive decline and depression. Using neuronal-specific MCU knockout mice (MCU−/−ΔN), we demonstrate that neuronal MCU deficiency reduced hippocampal excitability in vivo. Furthermore, in vitro analyses of hippocampal glioneuronal cells reveal no change in total Ca2+ levels but differences in intracellular Ca2+ handling. MCU−/−ΔN reduces ROS production, declines metabolic fluxes, and consequently prevents glioneuronal cell death. This effect was also observed under pathological conditions, such as the low magnesium culture model of seizure-like activity or excitotoxic glutamate stimulation, whereby MCU−/−ΔN reduces ROS levels and suppresses Ca2+ overload seen in WT cells. This study highlights the importance of MCU at the interface of Ca2+ handling and metabolism as a mediator of stress-related mitochondrial dysfunction, which indicates the modulation of MCU as a potential target for future antiepileptogenic therapy. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, which are characterized by progressive neuronal loss and cognitive decline, are a significant concern for the aging population. Neuroinflammation, a shared characteristic of these diseases, is implicated in their pathogenesis. This article briefly summarizes the role of magnesium, an essential mineral involved in numerous enzymatic reactions and critical for neuronal bioactivity, in the context of neuroinflammation and cognitive decline. The potential neuroprotective effects of magnesium, including the mechanisms of neuroprotection by magnesium through maintaining neuronal ion homeostasis, reducing inflammation, and preventing excitotoxicity, are also described. Additionally, we discuss the impact of inadequate magnesium on neuroinflammation and its potential as a therapeutic agent for attenuating cognitive decline to improve neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

The objective of this review was to verify the therapeutic effect of polysaccharides derived from algae in neurodegenerative disease models involving the basal ganglia. To achieve this goal, a literature search was conducted in PubMed, Science Direct, Scopus, Web of Science, Embase, and Google Scholar databases. The descriptors "neuroprotective or neural regenerative or immunomodulatory activity or neuroprotection," "polysaccharide or carbohydrate or carbohydrate polymers," "marine algae or seaweed," and "basal ganglia" according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology were used. This methodology involved the steps of searching, pre-selection, and inclusion of articles. A total of 737 records were identified. Following the data analysis, 698 studies were excluded, resulting in a final sample of 8 studies. Species such as Turbinaria decurrens, Gracilaria cornea, Chlorella pyrenoidosa, Arthrospira (Spirulina) platensis, Fucus vesiculosus, and Laminaria japonica have demonstrated significant neuroprotective effects. This review suggests that polysaccharides derived from marine algae possess therapeutic potential for neuroprotection, modulation of inflammation, and amelioration of functional deficits. Their use in neurodegenerative disease models warrants further consideration. [ABSTRACT FROM AUTHOR]

The editorial discusses the increasing prevalence of neurodegenerative disorders globally, emphasizing the need for advancements in diagnostic methods, innovative therapies, and prevention strategies. It covers a range of disorders like Alzheimer's, Parkinson's, and ALS, highlighting the complex interplay of genetic, epigenetic, and environmental factors in their development. The document also explores new treatment targets and strategies, focusing on the role of copper, genetic risk factors like APOE4, and lipid mediators in disease pathology. Additionally, it discusses the importance of biomarkers for early detection and potential personalized treatments for neurodegenerative diseases. [Extracted from the article]

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The neurotoxicant trimethyltin (TMT) triggers cognitive impairment and hippocampal neurodegeneration. TMT is a useful research tool for the study of Alzheimer's disease (AD) pathogenesis and treatment. Although the antidiabetic agent metformin has shown promising neuroprotective effects, however, its precise modes of action in neurodegenerative disorders need to be further elucidated. In this study, we investigated whether metformin can mitigate TMT cognition impairment and hippocampal neurodegeneration. To induce an AD-like phenotype, TMT was injected i.p. (8 mg/kg) and metformin was administered daily p.o. for 3 weeks at 200 mg/kg. Our results showed that metformin administration to the TMT group mitigated learning and memory impairment in Barnes maze, novel object recognition (NOR) task, and Y maze, attenuated hippocampal oxidative, inflammatory, and cell death/pyroptotic factors, and also reversed neurodegeneration-related proteins such as presenilin 1 and p-Tau. Hippocampal level of AMP-activated protein kinase (AMPK) as a key regulator of energy homeostasis was also improved following metformin treatment. Additionally, metformin reduced hippocampal acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP)-positive reactivity, and prevented the loss of CA1 pyramidal neurons. This study showed that metformin mitigated TMT-induced neurodegeneration and this may pave the way to develop new therapeutics to combat against cognitive deficits under neurotoxic conditions. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) triggers a cascade of intricate molecular and cellular changes that determine the outcome. In this study, we resolve the spatiotemporal organization of the injured mouse spinal cord and quantitatively assess in situ cell-cell communication following SCI. By analyzing existing single-cell RNA sequencing datasets alongside our spatial data, we delineate a subpopulation of Igfbp2 -expressing astrocytes that migrate from the white matter (WM) to gray matter (GM) and become reactive upon SCI, termed Astro-GMii. Further, Igfbp2 upregulation promotes astrocyte migration, proliferation, and reactivity, and the secreted IGFBP2 protein fosters neurite outgrowth. Finally, we show that IGFBP2 significantly reduces neuronal loss and remarkably improves the functional recovery in a mouse model of SCI in vivo. Together, this study not only provides a comprehensive molecular atlas of SCI but also exemplifies how this rich resource can be applied to endow cells and genes with functional insight and therapeutic potential. [Display omitted] • A comprehensive and dynamic molecular atlas of the spinal cord after acute injury • In situ depiction of cell-cell communication following spinal cord injury (SCI) • Spatial delineation of SCI-induced, WM-to-GM migrating Igfbp2 + -astrocytes • IGFBP2 treatment improves neuronal survival and functional outcomes of SCI in vivo Wang et al. conducted a comprehensive spatial transcriptomic analysis that provides a rich resource and a useful bioinformatic toolkit for disentangling the spatiotemporal re-organization of the injured spinal cord. They further spatially identified a subpopulation of injury-induced migrating astrocytes that secrete IGFBP2, which exhibits potent neuroprotection following SCI. [ABSTRACT FROM AUTHOR]

The infant gut microbiota undergoes significant changes during early life, which are essential for immune system maturation, nutrient absorption, and metabolic programming. Among the various microbial metabolites, shortchain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, produced through the fermentation of dietary fibers by gut bacteria, have emerged as critical modulators of host-microbiota interactions. SCFAs serve as energy sources for colonic cells and play pivotal roles in regulating immune responses, maintaining gut barrier integrity, and influencing systemic metabolic pathways. Recent research highlights the potential neuroprotective effects of SCFAs in pediatric populations. Disruptions in gut microbiota composition and SCFA production are increasingly associated with a range of pediatric health issues, including obesity, allergic disorders, inflammatory bowel disease (IBD), and neurodevelopmental disorders. This review synthesizes current knowledge on the role of microbiota-derived SCFAs in pediatric health, emphasizing their contributions from gut development to neuroprotection. It also underscores the need for further research to unravel the precise mechanisms by which SCFAs influence pediatric health and to develop targeted interventions that leverage SCFAs for therapeutic benefits. [ABSTRACT FROM AUTHOR]

During focal ischemia, neurons can use lactate as an alternative source of energy through its oxidation into pyruvate by the lactate dehydrogenase (LDH). After cardiac arrest, the neurological consequences of this phenomenon are unknown. Experimental study. Experimental laboratory. Male New-Zealand rabbits. Animals were surgically instrumented and randomly divided into five groups receiving short infusion duration of either lactate or pyruvate or a pre-cardiac arrest infusion of oxamate (an inhibitor of the lactate dehydrogenase) or injection of fluorocitrate (an inhibitor of astrocytic tricarboxylic acid), or Saline (lactate, pyruvate, Oxa, FC and Control groups, respectively). After randomization, animals were submitted to 10 min of ventricular fibrillation and subsequent resuscitation. All animals were then either followed during 4 h, for the evaluation of the cerebral net uptake and concentrations of metabolites by microdialysis (n = 6 in each experimental group, n = 12 in control group), or during 48 h for the evaluation of their neurological outcome (n = 7 in each groups and n = 14 in control group). Cardiac arrest was associated with a dramatic increase in cerebral net uptake of lactate during 120 min after resuscitation, which was increased by lactate or pyruvate administration. This was associated with an increase in the mean neurological dysfunction score (66.7 ± 4.7, 79.0 ± 4.5 vs 57.7 ± 1.5 in Lactate, Pyruvate and Control group respectively) at 48 h after cardiac arrest. Oxamate and FC administration were associated with a lower lactate cerebral uptake after cardiac arrest and with an improvement of the neurological recovery (28.85 ± 9.4, 23.86 ± 6.2 vs 57.7 ± 1.5 in Oxa, FC and Control group respectively). After cardiac arrest, immediate isotonic lactate or pyruvate administration is deleterious. Pre-cardiac arrest LDH inhibition was potently neuroprotective in this setting. [ABSTRACT FROM AUTHOR]

BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining "staple" and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection. [Display omitted] • Hydrocarbon staple scanning yielded optimal BCL-w BH4 domain binders of IP3R1 • Molecular dynamics simulations identified a BH4-binding site in ARM2 of IP3R1 • Point mutagenesis revealed the binding determinants for BH4 interaction • A lead stapled BCL-w BH4 peptide protects axons from chemo-induced degeneration Tang et al. report that staple and alanine scanning of the BCL-w BH4 domain revealed binding determinants for targeting IP3R1 by interaction with a surface groove on ARM2, as predicted by molecule dynamics simulations. A lead construct protected axons from paclitaxel-induced degeneration, with point mutagenesis impairing IP3R1 interaction and neuroprotection. [ABSTRACT FROM AUTHOR]

This review explores the potential health benefits and applications of phenolic secoiridoids derived from olive oil by-products in the prevention of Alzheimer's disease (AD). As reviewed herein, polyphenols, such as epigallocatechin-3-gallate, epicatechin, and resveratrol, show in vitro and in vivo antioxidant, anti-inflammatory, and neuroprotective properties, and are particularly relevant in the context of AD, a leading cause of dementia globally. The olive oil industry, particularly in the Mediterranean region, produces significant amounts of waste, including leaves, pomace, and wastewater, which pose environmental challenges but also offer an untapped source of bioactive compounds. Despite promising in vitro and in vivo studies indicating that olive-derived polyphenols, such as oleuropein and hydroxytyrosol, may mitigate AD pathology, human clinical trials remain limited. The variability in extraction methods and the complex nature of AD further complicate research. Future studies should focus on standardizing the protocols and conducting robust clinical trials to fully assess the therapeutic potential of these compounds. This approach not only supports the development of new treatments for AD but also promotes environmental sustainability by valorizing olive oil industry waste. [ABSTRACT FROM AUTHOR]

Neuroinflammation is a symptom of different neurodegenerative diseases, and growing interest is directed towards active drug development for the reduction of its negative effects. The anti-inflammatory activity of polyunsaturated fatty acids, eicosapentaenoic (EPA), docosahexaenoic (DHA), and their amide derivatives was largely investigated on some neural cells. Herein, we aimed to elucidate the protective role of both EPA and DHA and the corresponding N-ethanolamides EPA-EA and DHA-EA on neonatal mouse Olfactory Ensheathing Cells (OECs) after exposition to lipopolysaccharide (LPS)-induced neuroinflammation. To verify their anti-inflammatory effect and cell morphological features on OECs, the expression of IL-10 cytokine, and cytoskeletal proteins (vimentin and GFAP) was evaluated by immunocytochemical procedures. In addition, MTT assays, TUNEL, and mitochondrial health tests were carried out to assess their protective effects on OEC viability. Our results highlight a reduction in GFAP and vimentin expression in OECs exposed to LPS and treated with EPA or DHA or EPA-EA or DHA-EA in comparison with OECs exposed to LPS alone. We observed a protective role of EPA and DHA on cell morphology, while the amides EPA-EA and DHA-EA mainly exerted a superior anti-inflammatory effect compared to free acids. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are linked to the process of neurodegeneration. This can be caused by several mechanisms, including inflammation and accumulation of reactive oxygen species. Despite their high incidence, there is still no effective treatment or cure for these diseases. Cyanobacteria have been seen as a possible source for new compounds with anti-inflammatory and antioxidant potential, such as polysaccharides (sacran), phycobiliproteins (phycocyanin) and lipopeptides (honaucins and malyngamides), which can be interesting to combat neurodegeneration. As a promising case of success, Arthrospira (formerly Spirulina) has revealed a high potential for preventing neurodegeneration. Additionally, advantageous culture conditions and sustainable production of cyanobacteria, which are allied to the development of genetic, metabolic, and biochemical engineering, are promising. The aim of this review is to compile and highlight research on the anti-inflammatory and antioxidant potential of cyanobacteria with focus on the application as neuroprotective agents. Also, a major goal is to address essential features that brand cyanobacteria as an ecoefficient and economically viable option, linking health to sustainability. [ABSTRACT FROM AUTHOR]

Background: The components of donor blood themselves have the potential to initiate a systemic inflammatory response and exacerbate neuroinflammation, resulting in subsequent cerebral injury. The aim of this study was to establish the role of transfusion in the development of cerebral injury during the correction of congenital heart defects in children. Material and Methods: A total of 78 patients aged from 1 to 78 months, with body weights ranging from 3.3 to 21.5 kg, were investigated. Biomarkers of cerebral injury and systemic inflammatory response were studied at three time points. First: prior to the surgical intervention. Second: after the completion of cardiopulmonary bypass. Third: 16 h after the conclusion of the surgery. Results: The strongest correlation was found for S-100-β protein with the volume of transfusion at the second (Rho = 0.48, p = 0.00065) and third time points (Rho = 0.36, p = 0.01330). Neuron-specific enolase demonstrated a similar trend: Rho = 0.41 and p = 0.00421 after the completion of cardiopulmonary bypass. Conclusions: The use of red blood cell suspension and its dosage per kilogram of body weight correlated with the biomarkers of cerebral injury and systemic inflammatory response with moderate to significant strength. [ABSTRACT FROM AUTHOR]