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Discovering new drugs to treat central nervous system (CNS) disease involves establishing high-throughput screening (HTS) formats for central phenotypes such as neuroinflammation, oxidative stress, pathological proteins, hyperexcitability, and neuroplasticity. A range of complex and patient-based models exist to discover new drugs for these phenotypes; however, certain trade-offs between clinical relevance and scalability need to be carefully considered. While most CNS drug discovery studies have employed chemogenomic-based compound libraries, new fragment-based approaches are emerging that offer distinct advantages. The design of the screening cascade for hit-to-lead studies is often key to the success of CNS phenotypic drug discovery, with experimental and artificial intelligence (AI) target identification approaches now playing an important role in this process. Central nervous system (CNS) drug development is plagued by high clinical failure rate. Phenotypic assays promote clinical translation of drugs by reducing complex brain diseases to measurable, clinically valid phenotypes. We critique recent platforms integrating patient-derived brain cells, which most accurately recapitulate CNS disease phenotypes, with higher throughput models, including immortalized cells, to balance validity and scalability. These platforms were screened with conventional commercial chemogenomic compound libraries. We explore emerging library curation strategies to improve hit rate and quality, and screening novel fragment libraries as alternatives, for more tractable drug target deconvolution. The clinically relevant models used in these platforms could harbor important, unidentified drug targets, so we review evolving agnostic target deconvolution approaches, including chemical proteomics and artificial intelligence (AI), which aid in phenotypic screening hit mechanism elucidation, thereby facilitating rational hit-to-drug optimization. [ABSTRACT FROM AUTHOR]

Citicoline, a compound produced naturally in small amounts in the human body, assumes a pivotal role in phosphatidylcholine synthesis, a dynamic constituent of membranes of neurons. Across diverse models of brain injury and neurodegeneration, citicoline has demonstrated its potential through neuroprotective and anti‐inflammatory effects. This review aims to elucidate citicoline's anti‐inflammatory mechanism and its clinical implications in conditions such as ischemic stroke, head trauma, glaucoma, and age‐associated memory impairment. Citicoline's anti‐inflammatory prowess is rooted in its ability to stabilize cellular membranes, thereby curbing the excessive release of glutamate—a pro‐inflammatory neurotransmitter. Moreover, it actively diminishes free radicals and inflammatory cytokines productions, which could otherwise harm neurons and incite neuroinflammation. It also exhibits the potential to modulate microglia activity, the brain's resident immune cells, and hinder the activation of NF‐κB, a transcription factor governing inflammatory genes. Clinical trials have subjected citicoline to rigorous scrutiny in patients grappling with acute ischemic stroke, head trauma, glaucoma, and age‐related memory impairment. While findings from these trials are mixed, numerous studies suggest that citicoline could confer improvements in neurological function, disability reduction, expedited recovery, and cognitive decline prevention within these cohorts. Additionally, citicoline boasts a favorable safety profile and high tolerability. In summary, citicoline stands as a promising agent, wielding both neuroprotective and anti‐inflammatory potential across a spectrum of neurological conditions. However, further research is imperative to delineate the optimal dosage, treatment duration, and underlying mechanisms. Moreover, identifying specific patient subgroups most likely to reap the benefits of citicoline as a new therapy remains a critical avenue for exploration. [ABSTRACT FROM AUTHOR]

Abstract Background Epilepsy in dogs and humans is associated with blood‐brain barrier (BBB) dysfunction (BBBD), which may involve dysfunction of tight junction (TJ) proteins, matrix metalloproteases, and astrocytes. Imaging techniques to assess BBB integrity, to identify potential treatment strategies, have not yet been evaluated in veterinary medicine. Hypothesis Some dogs with idiopathic epilepsy (IE) will exhibit BBBD. Identifying BBBD may improve antiepileptic treatment in the future. Animals Twenty‐seven dogs with IE and 10 healthy controls. Methods Retrospective, prospective cohort study. Blood‐brain barrier permeability (BBBP) scores were calculated for the whole brain and piriform lobe of all dogs by using dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) and subtraction enhancement analysis (SEA). Matrix metalloproteinase‐9 (MMP9) activity in serum and cerebrospinal fluid (CSF) was measured and its expression in the piriform lobe was examined using immunofluorescent staining. Gene expression of TJ proteins and astrocytic transporters was analyzed in the piriform lobe. Results The DCE‐MRI analysis of the piriform lobe identified higher BBBP score in the IE group when compared with controls (34.5% vs 26.5%; P = .02). Activity and expression of MMP9 were increased in the serum, CSF, and piriform lobe of IE dogs as compared with controls. Gene expression of Kir4.1 and claudin‐5 in the piriform lobe of IE dogs was significantly lower than in control dogs. Conclusions and Clinical Importance Our findings demonstrate BBBD in dogs with IE and were supported by increased MMP9 activity and downregulation of astrocytic potassium channels and some TJ proteins. Blood brain barrier dysfunction may be a novel antiepileptic therapy target.

Background: Epilepsy in dogs and humans is associated with blood‐brain barrier (BBB) dysfunction (BBBD), which may involve dysfunction of tight junction (TJ) proteins, matrix metalloproteases, and astrocytes. Imaging techniques to assess BBB integrity, to identify potential treatment strategies, have not yet been evaluated in veterinary medicine. Hypothesis: Some dogs with idiopathic epilepsy (IE) will exhibit BBBD. Identifying BBBD may improve antiepileptic treatment in the future. Animals: Twenty‐seven dogs with IE and 10 healthy controls. Methods: Retrospective, prospective cohort study. Blood‐brain barrier permeability (BBBP) scores were calculated for the whole brain and piriform lobe of all dogs by using dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) and subtraction enhancement analysis (SEA). Matrix metalloproteinase‐9 (MMP9) activity in serum and cerebrospinal fluid (CSF) was measured and its expression in the piriform lobe was examined using immunofluorescent staining. Gene expression of TJ proteins and astrocytic transporters was analyzed in the piriform lobe. Results: The DCE‐MRI analysis of the piriform lobe identified higher BBBP score in the IE group when compared with controls (34.5% vs 26.5%; P =.02). Activity and expression of MMP9 were increased in the serum, CSF, and piriform lobe of IE dogs as compared with controls. Gene expression of Kir4.1 and claudin‐5 in the piriform lobe of IE dogs was significantly lower than in control dogs. Conclusions and Clinical Importance: Our findings demonstrate BBBD in dogs with IE and were supported by increased MMP9 activity and downregulation of astrocytic potassium channels and some TJ proteins. Blood brain barrier dysfunction may be a novel antiepileptic therapy target. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) is a tailored system of capillary endothelial cells intermixed with tight junctions and adherent junctions that regulates the transport of various materials and substances between the blood vasculature and the central nervous system (CNS). However, in cases of brain diseases, BBB's protective and regulatory effects hamper therapeutics from reaching affected sites in sufficient quantities. This has so far been a leading challenge in treating CNS diseases and disorders. For this problem to be overcome, recent research has sought to develop novel modalities to achieve efficient therapy and alleviate associated symptoms. Therefore, numerous strategies have operated in recent years to address the limitations of traditional and invasive methods, including poor brain penetration and serious side effects. As a desperately in‐demand technology, nanotheranostics has particularly shown promising results. Herein, this review reports recent advancements in CNS nanotheranostics and novel techniques and nanotechnology‐based strategies developed for treating neurodegenerative disorders. The study provides comprehensive data on the subject to be used for future studies for the therapy and management of CNS disorders and diseases. [ABSTRACT FROM AUTHOR]

Purinergic P2X receptors, particularly P2X7 and P2X4, are pivotal in brain functioning and pathology, affecting various central nervous system diseases. This review delves into P2X receptors' roles in various pathologies, including ischemia, epilepsy, COVID-19, some neurodegenerative and psychiatric disorders. P2X7's involvement in neuroinflammatory processes through the activation of the NLRP3 inflammasome highlights its significant role in corresponding pathologies and their treatment, as seen in studies using selective receptor antagonists like JNJ-55308942. Similarly, P2X4 receptor, which has the higher sensitivity to ATP than P2X7, plays critical roles in the inflammatory response poststroke and show therapeutic potential across a spectrum of neurological conditions. The emerging significance of P2X receptors in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis, showcasing their influence on disease progression and potential as therapeutic targets is also briefly discussed. In psychiatric disorders, including major depressive disorder and autism spectrum disorders, P2X receptors contribute to pathology through mechanisms involving inflammation and neuroimmune response modulation. In summary, the recent data underscores the importance of P2X receptors in CNS health and disease, advocating for further exploration to uncover novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis. [ABSTRACT FROM AUTHOR]

Mirtazapine (MTZ) is an antidepressant drug with an exceptional pharmacological profile. It also has an excellent safety and tolerability profile. The present review provides a pharmacological update on MTZ and summarizes the research findings of MTZ's effects on different diseases. MTZ is hypothesized to have antidepressant effects because of the synergy between noradrenergic and serotonergic actions and is effective in treating major depressive disorder and depression associated with epilepsy, Alzheimer's disease, stroke, cardiovascular disease, and respiratory disease. In cancer patients, MTZ significantly reduced sadness, nausea, sleep disruption, and pain and improved quality of life. Also, it has promising effects on Parkinson's disease, schizophrenia, dysthymia, social anxiety disorder, alcohol dependency, posttraumatic stress disorder, panic disorder, pain syndromes, obsessive–compulsive disorder, and sleep disorders. Additionally, MTZ is potentially therapeutic in different situations associated with depression, such as liver, kidney, cardiovascular, respiratory, infertility, heavy metal-induced neurotoxicity, and pruritus. Potent antioxidative, anti-inflammatory, and anti-apoptotic bioactivities mediate these promising effects. These positive outcomes of the scientific investigations motivate more and more clinical trials for a golden exceptional antidepressant in different conditions. [ABSTRACT FROM AUTHOR]

Inflammasomes are important modulators of inflammation. Dysregulation of inflammasomes can enhance vulnerability to conditions such as neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Among various inflammasomes, Nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) is the best-characterized inflammasome related to inflammatory and neurodegenerative diseases. NLRP3 is an intracellular sensor that recognizes pathogen-associated molecular patterns and damage-associated patterns resulting in the assembly and activation of NLRP3 inflammasome. The NLRP3 inflammasome includes sensor NLRP3, adaptor apoptosis-associated speck-like protein (ASC), and effector cysteine protease procaspase-1 that plays an imperative role in caspase-1 stimulation which further initiates a secondary inflammatory response. Regulation of NLRP3 inflammasome ameliorates NLRP3-mediated diseases. Much effort has been invested in studying the activation, and exploration of specific inhibitors and epigenetic mechanisms controlling NLRP3 inflammasome. This review gives an overview of the established NLRP3 inflammasome assembly, its brief molecular mechanistic activations as well as a current update on specific and non-specific NLRP3 inhibitors that could be used in NLRP3-mediated diseases. We also focused on the recently discovered epigenetic mechanisms mediated by DNA methylation, histone alterations, and microRNAs in regulating the activation and expression of NLRP3 inflammasome, which has resulted in a novel method of gaining insight into the mechanisms that modulate NLRP3 inflammasome activity and introducing potential therapeutic strategies for CNS disorders. [ABSTRACT FROM AUTHOR]

Malignant tumors and central nervous system (CNS) disorders are intricately linked to a process known as ''aberrant cell cycle re-entry,'' which plays a critical role in the progression of these diseases. Addressing the dysregulation in cell cycles offers a promising therapeutic approach for cancers and CNS disorders. MicroRNAs (miRNAs) play a crucial role as regulators of gene expression in cell cycle transitions, presenting a promising therapeutic avenue for treating these disorders and their comorbidities. This review consolidates the progress made in the last three years regarding miRNA-based treatments for diseases associated with aberrant cell cycle re-entry. It encompasses exploring fundamental mechanisms and signaling pathways influenced by miRNAs in cancers and CNS disorders, particularly focusing on the therapeutic effects of exosome-derived miRNAs. The review also identifies specific miRNAs implicated in comorbidity of cancers and CNS disorders, discusses the future potential of miRNA reagents in managing cell cycle-related diseases.

Central nervous system (CNS) disorders exhibit exceedingly intricate pathogenic mechanisms. Pragmatic and effective solutions remain elusive, significantly compromising human life and health. Activating transcription factor 4 (ATF4) participates in the regulation of multiple pathophysiological processes, including CNS disorders. Considering the widespread involvement of ATF4 in the pathological process of CNS disorders, the targeted regulation of ATF4 by plant-derived bioactive compounds (PDBCs) may become a viable strategy for the treatment of CNS disorders. However, the regulatory relationship between PDBCs and ATF4 remains incompletely understood. Here, we aimed to comprehensively review the studies on PDBCs targeting ATF4 to ameliorate CNS disorders, thereby offering novel directions and insights for the treatment of CNS disorders. A computerized search was conducted on PubMed, Embase, Web of Science, and Google Scholar databases to identify preclinical experiments related to PDBCs targeting ATF4 for the treatment of CNS disorders. The search timeframe was from the inception of the databases to December 2023. Two assessors conducted searches using the keywords ''ATF4,'' ''Central Nervous System,'' ''Neurological,'' ''Alzheimer's disease,'' ''Parkinson's Disease,'' ''Stroke,'' ''Spinal Cord Injury,'' ''Glioblastoma,'' ''Traumatic Brain Injury,'' and ''Spinal Cord Injury.'' Overall, 31 studies were included, encompassing assessments of 27 PDBCs. Combining results from in vivo and in vitro studies, we observed that these PDBCs, via ATF4 modulation, prevent the deposition of amyloid-like fibers such as Aβ, tau, and α-synuclein. They regulate ERS, reduce the release of inflammatory factors, restore mitochondrial membrane integrity to prevent oxidative stress, regulate synaptic plasticity, modulate autophagy, and engage anti-apoptotic mechanisms. Consequently, they exert neuroprotective effects in CNS disorders. Numerous PDBCs targeting ATF4 have shown potential in facilitating the restoration of CNS functionality, thereby presenting expansive prospects for the treatment of such disorders. However, future endeavors necessitate high-quality, large-scale, and comprehensive preclinical and clinical studies to further validate this therapeutic potential.

Abstract NAD(P)H Quinone Dehydrogenase 1 (NQO1) plays a pivotal role in the regulation of neuronal function and synaptic plasticity, cellular adaptation to oxidative stress, neuroinflammatory and degenerative processes, and tumorigenesis in the central nervous system (CNS). Impairment of the NQO1 activity in the CNS can result in abnormal neurotransmitter release and clearance, increased oxidative stress, and aggravated cellular injury/death. Furthermore, it can cause disturbances in neural circuit function and synaptic neurotransmission. The abnormalities of NQO1 enzyme activity have been linked to the pathophysiological mechanisms of multiple neurological disorders, including Parkinson's disease, Alzheimer's disease, epilepsy, multiple sclerosis, cerebrovascular disease, traumatic brain injury, and brain malignancy. NQO1 contributes to various dimensions of tumorigenesis and treatment response in various brain tumors. The precise mechanisms through which abnormalities in NQO1 function contribute to these neurological disorders continue to be a subject of ongoing research. Building upon the existing knowledge, the present study reviews current investigations describing the role of NQO1 dysregulations in various neurological disorders. This study emphasizes the potential of NQO1 as a biomarker in diagnostic and prognostic approaches, as well as its suitability as a target for drug development strategies in neurological disorders.

NAD(P)H Quinone Dehydrogenase 1 (NQO1) plays a pivotal role in the regulation of neuronal function and synaptic plasticity, cellular adaptation to oxidative stress, neuroinflammatory and degenerative processes, and tumorigenesis in the central nervous system (CNS). Impairment of the NQO1 activity in the CNS can result in abnormal neurotransmitter release and clearance, increased oxidative stress, and aggravated cellular injury/death. Furthermore, it can cause disturbances in neural circuit function and synaptic neurotransmission. The abnormalities of NQO1 enzyme activity have been linked to the pathophysiological mechanisms of multiple neurological disorders, including Parkinson's disease, Alzheimer's disease, epilepsy, multiple sclerosis, cerebrovascular disease, traumatic brain injury, and brain malignancy. NQO1 contributes to various dimensions of tumorigenesis and treatment response in various brain tumors. The precise mechanisms through which abnormalities in NQO1 function contribute to these neurological disorders continue to be a subject of ongoing research. Building upon the existing knowledge, the present study reviews current investigations describing the role of NQO1 dysregulations in various neurological disorders. This study emphasizes the potential of NQO1 as a biomarker in diagnostic and prognostic approaches, as well as its suitability as a target for drug development strategies in neurological disorders. [ABSTRACT FROM AUTHOR]

In recent years, there have been a growing number of small and large molecules that could be used to treat diseases of the central nervous system (CNS). Nose-to-brain delivery can be a potential option for the direct transport of molecules from the nasal cavity to different brain areas. This review aims to provide a compilation of current approaches regarding drug delivery to the CNS via the nose, with a focus on biologics. The review also includes a discussion on the key benefits of nasal delivery as a promising alternative route for drug administration and the involved pathways or mechanisms. This article reviews how the application of various auxiliary agents, such as permeation enhancers, mucolytics, in situ gelling/mucoadhesive agents, enzyme inhibitors, and polymeric and lipid-based systems, can promote the delivery of large molecules in the CNS. The article also includes a discussion on the current state of intranasal formulation development and summarizes the biologics currently in clinical trials. It was noted that significant progress has been made in this field, and these are currently being applied to successfully transport large molecules to the CNS via the nose. However, a deep mechanistic understanding of this route, along with the intimate knowledge of various excipients and their interactions with the drug and nasal physiology, is still necessary to bring us one step closer to developing effective formulations for nasal–brain drug delivery. [ABSTRACT FROM AUTHOR]

The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis.

Abstract Case Description We describe a case of presumptive acquired systemic lupus erythematosus secondary to phenobarbital administration in a dog, which resolved with withdrawal of the drug. Clinical Findings A 3.5 year‐old poodle presented to a veterinary teaching hospital for Tier 1 idiopathic epilepsy and was treated with phenobarbital. The dog experienced fever, multiple cytopenias, and proteinuria in conjunction with a positive antinuclear antibody (ANA) titer. Diagnostics Serial CBCs, urine protein : creatinine ratios, and sternal bone marrow aspirates were performed to evaluate improvement. Treatment and Outcome Phenobarbital was withdrawn and levetiracetam initiated. All abnormalities resolved with supportive care, without initiation of immunosuppressive drugs. All cytopenias and proteinuria resolved and ANA test results became negative within 3 months. The patient recovered and did well clinically. Clinical Relevance Systemic lupus erythematosus is a disease of multiple autoimmune syndromes occurring concurrently or sequentially in conjunction with the presence of circulating ANA. It has been well described in dogs as an idiopathic condition, but in human medicine may occur secondary to drug reactions (drug‐associated lupus) including as a reaction to phenobarbital. The findings in our case are consistent with the criteria for drug‐induced lupus in humans and we suggest it as the first report of phenobarbital‐induced lupus in a dog.

Abstract Background In humans, the T2‐weighted (T2W)—fluid‐attenuated inversion recovery (FLAIR) mismatch sign (T2FMM) is a specific imaging biomarker for the isocitrate dehydrogenase 1 (IDH1)‐mutated, 1p/19q non‐codeleted low‐grade astrocytomas (LGA). The T2FMM is characterized by a homogeneous hyperintense T2W signal and a hypointense signal with a hyperintense peripheral rim on FLAIR sequences. In gliomas in dogs, the T2FMM has not been described. Hypotheses/Objectives In dogs with focal intra‐axial brain lesions, T2FMM will discriminate gliomas from other lesions. The T2FMM will be associated with the LGA phenotype and presence of microcysts on histopathology. Interobserver agreement for T2FMM magnetic resonance imaging (MRI) features will be high. Animals One hundred eighty‐six dogs with histopathologically diagnosed focal intra‐axial lesions on brain MRI including oligodendrogliomas (n = 90), astrocytomas (n = 47), undefined gliomas (n = 9), cerebrovascular accidents (n = 33), and inflammatory lesions (n = 7). Methods Two blinded raters evaluated the 186 MRI studies and identified cases with the T2FMM. Histopathologic and immunohistochemical slides of T2FMM cases were evaluated for morphologic features and IDH1‐mutations and compared to cases without the T2FMM. Gene expression analyses were performed on a subset of oligodendrogliomas (n = 10) with and without T2FMM. Results The T2FMM was identified in 14/186 (8%) of MRI studies, and all dogs with T2FMM had oligodendrogliomas (n = 12 low‐grade [LGO], n = 2 high‐grade [HGO]; P

Lysosomal storage diseases (LSDs) are caused by enzyme deficiency in the cellular lysosomal apparatus, leading to a pathological accumulation of undigested cellular material (proteins, lipids or carbohydrates) and eventual tissue damage. Clinically and etiologically diverse, this group includes over 70 presently recognized hereditary conditions that have no effective therapy known to date. Most common manifestations of LSDs are brain lesions leading to various neurological deficits. Thus, the search for therapeutic strategies targeting these disorders represents an urgent unmet biomedical task, also necessitating the use of appropriate and valid experimental (animal) models. Here, we discuss the available models of LSDs and the applicability of rodents and zebrafish as model organisms for probing these pathologies. [ABSTRACT FROM AUTHOR]

Case Description: We describe a case of presumptive acquired systemic lupus erythematosus secondary to phenobarbital administration in a dog, which resolved with withdrawal of the drug. Clinical Findings: A 3.5 year‐old poodle presented to a veterinary teaching hospital for Tier 1 idiopathic epilepsy and was treated with phenobarbital. The dog experienced fever, multiple cytopenias, and proteinuria in conjunction with a positive antinuclear antibody (ANA) titer. Diagnostics: Serial CBCs, urine protein : creatinine ratios, and sternal bone marrow aspirates were performed to evaluate improvement. Treatment and Outcome: Phenobarbital was withdrawn and levetiracetam initiated. All abnormalities resolved with supportive care, without initiation of immunosuppressive drugs. All cytopenias and proteinuria resolved and ANA test results became negative within 3 months. The patient recovered and did well clinically. Clinical Relevance: Systemic lupus erythematosus is a disease of multiple autoimmune syndromes occurring concurrently or sequentially in conjunction with the presence of circulating ANA. It has been well described in dogs as an idiopathic condition, but in human medicine may occur secondary to drug reactions (drug‐associated lupus) including as a reaction to phenobarbital. The findings in our case are consistent with the criteria for drug‐induced lupus in humans and we suggest it as the first report of phenobarbital‐induced lupus in a dog. [ABSTRACT FROM AUTHOR]

Abstract Background Blood‐brain barrier (BBB) permeability can be assessed quantitatively using advanced imaging analysis. Hypothesis/Objectives Quantification and characterization of blood‐brain barrier dysfunction (BBBD) patterns in dogs with brain tumors can provide useful information about tumor biology and assist in distinguishing between gliomas and meningiomas. Animals Seventy‐eight hospitalized dogs with brain tumors and 12 control dogs without brain tumors. Methods In a 2‐arm study, images from a prospective dynamic contrast‐enhanced (DCE; n = 15) and a retrospective archived magnetic resonance imaging study (n = 63) were analyzed by DCE and subtraction enhancement analysis (SEA) to quantify BBB permeability in affected dogs relative to control dogs (n = 6 in each arm). For the SEA method, 2 ranges of postcontrast intensity differences, that is, high (HR) and low (LR), were evaluated as possible representations of 2 classes of BBB leakage. BBB score was calculated for each dog and was associated with clinical characteristics and tumor location and class. Permeability maps were generated, using the slope values (DCE) or intensity difference (SEA) of each voxel, and analyzed. Results Distinctive patterns and distributions of BBBD were identified for intra‐ and extra‐axial tumors. At a cutoff of 0.1, LR/HR BBB score ratio yielded a sensitivity of 80% and specificity of 100% in differentiating gliomas from meningiomas. Conclusions and Clinical Importance Blood‐brain barrier dysfunction quantification using advanced imaging analyses has the potential to be used for assessment of brain tumor characteristics and behavior and, particularly, to help differentiating gliomas from meningiomas.

The association and interaction between the central nervous system (CNS) and enteric nervous system (ENS) is well established. Essentially ENS is the second brain, as we call it. We tried to understand the structure and function, to throw light on the functional aspect of neurons, and address various disease manifestations. We summarized how various neurological disorders influence the gut via the enteric nervous system and/or bring anatomical or physiological changes in the enteric nervous system or the gut and vice versa. It is known that stress has an effect on Gastrointestinal (GI) motility and causes mucosal erosions. In our literature review, we found that stress can also affect sensory perception in the central nervous system. Interestingly, we found that mutations in the neurohormone, serotonin (5-HT), would result in dysfunctional organ development and further affect mood and behavior. We focused on the developmental aspects of neurons and cognition and their relation to nutritional absorption via the gastrointestinal tract, the development of neurodegenerative disorders in relation to the alteration in gut microbiota, and contrariwise associations between CNS disorders and ENS. This paper further summarizes the synergetic relation between gastrointestinal and neuropsychological manifestations and emphasizes the need to include behavioral therapies in management plans. [ABSTRACT FROM AUTHOR]

Background: In humans, the T2‐weighted (T2W)—fluid‐attenuated inversion recovery (FLAIR) mismatch sign (T2FMM) is a specific imaging biomarker for the isocitrate dehydrogenase 1 (IDH1)‐mutated, 1p/19q non‐codeleted low‐grade astrocytomas (LGA). The T2FMM is characterized by a homogeneous hyperintense T2W signal and a hypointense signal with a hyperintense peripheral rim on FLAIR sequences. In gliomas in dogs, the T2FMM has not been described. Hypotheses/Objectives: In dogs with focal intra‐axial brain lesions, T2FMM will discriminate gliomas from other lesions. The T2FMM will be associated with the LGA phenotype and presence of microcysts on histopathology. Interobserver agreement for T2FMM magnetic resonance imaging (MRI) features will be high. Animals: One hundred eighty‐six dogs with histopathologically diagnosed focal intra‐axial lesions on brain MRI including oligodendrogliomas (n = 90), astrocytomas (n = 47), undefined gliomas (n = 9), cerebrovascular accidents (n = 33), and inflammatory lesions (n = 7). Methods: Two blinded raters evaluated the 186 MRI studies and identified cases with the T2FMM. Histopathologic and immunohistochemical slides of T2FMM cases were evaluated for morphologic features and IDH1‐mutations and compared to cases without the T2FMM. Gene expression analyses were performed on a subset of oligodendrogliomas (n = 10) with and without T2FMM. Results: The T2FMM was identified in 14/186 (8%) of MRI studies, and all dogs with T2FMM had oligodendrogliomas (n = 12 low‐grade [LGO], n = 2 high‐grade [HGO]; P <.001). Microcystic change was significantly associated with the T2FMM (P <.00001). In oligodendrogliomas with T2FMM, IDH1‐mutations or specific differentially expressed genes were not identified. Conclusion and Clinical Importance: The T2FMM can be readily identified on routinely obtained MRI sequences. It is a specific biomarker for oligodendroglioma in dogs, and was significantly associated with non‐enhancing LGO. [ABSTRACT FROM AUTHOR]

Background: Blood‐brain barrier (BBB) permeability can be assessed quantitatively using advanced imaging analysis. Hypothesis/Objectives: Quantification and characterization of blood‐brain barrier dysfunction (BBBD) patterns in dogs with brain tumors can provide useful information about tumor biology and assist in distinguishing between gliomas and meningiomas. Animals: Seventy‐eight hospitalized dogs with brain tumors and 12 control dogs without brain tumors. Methods: In a 2‐arm study, images from a prospective dynamic contrast‐enhanced (DCE; n = 15) and a retrospective archived magnetic resonance imaging study (n = 63) were analyzed by DCE and subtraction enhancement analysis (SEA) to quantify BBB permeability in affected dogs relative to control dogs (n = 6 in each arm). For the SEA method, 2 ranges of postcontrast intensity differences, that is, high (HR) and low (LR), were evaluated as possible representations of 2 classes of BBB leakage. BBB score was calculated for each dog and was associated with clinical characteristics and tumor location and class. Permeability maps were generated, using the slope values (DCE) or intensity difference (SEA) of each voxel, and analyzed. Results: Distinctive patterns and distributions of BBBD were identified for intra‐ and extra‐axial tumors. At a cutoff of 0.1, LR/HR BBB score ratio yielded a sensitivity of 80% and specificity of 100% in differentiating gliomas from meningiomas. Conclusions and Clinical Importance: Blood‐brain barrier dysfunction quantification using advanced imaging analyses has the potential to be used for assessment of brain tumor characteristics and behavior and, particularly, to help differentiating gliomas from meningiomas. [ABSTRACT FROM AUTHOR]

Progress in treating central nervous system (CNS) disorders is retarded owing to a limited understanding of brain disease pathology. Additionally, the blood–brain barrier (BBB) limits molecular entry into the brain. Many approaches for brain drug delivery to overcome the BBB, such as BBB permeability enhancement, transient BBB disruption, and direct surgical administration have been explored with limited success. Recent research has shown that direct vascular channels exist between the skull bone marrow and the meninges, allowing myeloid and lymphoid cells to migrate. We hypothesized that these direct channels may also allow brain drug delivery from the skull bone marrow to the brain. In this study, for the first time we propose intraosseous administration of drugs into the skull (intracalvariosseous [ICO]) as a novel approach for brain drug delivery via BBB bypassing routes. We tested the feasibility of the approach by applying nine representative compounds over thinned mouse skulls to simulate ICO and measuring the compound entry level in the brain compared to that after systemic administration. Surprisingly, we found that the skull is not completely impermeable to drug penetration into the brain and the tested compounds reached the brain tissue several tens‐to‐hundred times higher by ICO than systemic application. These findings suggest a role for the BBB bypassing route from skull to brain, apart from the systemic route, in the drug entry into the brain after ICO. This approach should be applicable to other CNS drugs and even BBB impermeable drugs. Overall ICO provides an innovative and advantageous pathway for effective treatment of brain diseases. [ABSTRACT FROM AUTHOR]

In recent years, there have been a growing number of small and large molecules that could be used to treat diseases of the central nervous system (CNS). Nose-to-brain delivery can be a potential option for the direct transport of molecules from the nasal cavity to different brain areas. This review aims to provide a compilation of current approaches regarding drug delivery to the CNS via the nose, with a focus on biologics. The review also includes a discussion on the key benefits of nasal delivery as a promising alternative route for drug administration and the involved pathways or mechanisms. This article reviews how the application of various auxiliary agents, such as permeation enhancers, mucolytics, in situ gelling/mucoadhesive agents, enzyme inhibitors, and polymeric and lipid-based systems, can promote the delivery of large molecules in the CNS. The article also includes a discussion on the current state of intranasal formulation development and summarizes the biologics currently in clinical trials. It was noted that significant progress has been made in this field, and these are currently being applied to successfully transport large molecules to the CNS via the nose. However, a deep mechanistic understanding of this route, along with the intimate knowledge of various excipients and their interactions with the drug and nasal physiology, is still necessary to bring us one step closer to developing effective formulations for nasal–brain drug delivery.

Abstract Progress in treating central nervous system (CNS) disorders is retarded owing to a limited understanding of brain disease pathology. Additionally, the blood–brain barrier (BBB) limits molecular entry into the brain. Many approaches for brain drug delivery to overcome the BBB, such as BBB permeability enhancement, transient BBB disruption, and direct surgical administration have been explored with limited success. Recent research has shown that direct vascular channels exist between the skull bone marrow and the meninges, allowing myeloid and lymphoid cells to migrate. We hypothesized that these direct channels may also allow brain drug delivery from the skull bone marrow to the brain. In this study, for the first time we propose intraosseous administration of drugs into the skull (intracalvariosseous [ICO]) as a novel approach for brain drug delivery via BBB bypassing routes. We tested the feasibility of the approach by applying nine representative compounds over thinned mouse skulls to simulate ICO and measuring the compound entry level in the brain compared to that after systemic administration. Surprisingly, we found that the skull is not completely impermeable to drug penetration into the brain and the tested compounds reached the brain tissue several tens‐to‐hundred times higher by ICO than systemic application. These findings suggest a role for the BBB bypassing route from skull to brain, apart from the systemic route, in the drug entry into the brain after ICO. This approach should be applicable to other CNS drugs and even BBB impermeable drugs. Overall ICO provides an innovative and advantageous pathway for effective treatment of brain diseases.

Disorders of central nervous system (CNS) disorders are considered serious health issues. The most common CNS diseases include neurodegenerative diseases, mental disorders, demyelinating disease, ischemia-reperfusion injury, and neuroinflammation. As a natural phenolic compound, hesperidin is a flavanone glycoside with various biological effects. Increasing evidence show that the growth of CNS diseases is hindered by hesperidin. Here, we have reviewed the related literature on neuropharmacological mechanisms for the preventive and therapeutic effects of hesperidin on CNS diseases. Several cellular and animal models have been developed to evaluate the underlying neuropharmacological mechanisms of hesperidin. Additionally, clinical evidence has confirmed its neuroprotective function. Hesperidin exerts its neuroprotective properties by decreasing neuro-inflammatory and apoptotic pathways. Hesperidin function has been studied in preclinical models for CNS diseases, but little is known about its definite effect in humans. Hesperidin can effectively alleviate depression and improve cognition and memory. It is urgent to explore and discover clinical trials for further confirmation of the neuroprotective efficacy of hesperidin and to evaluate its safety profile.

In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood–brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies. [ABSTRACT FROM AUTHOR]

Nowadays it is observed that the number of stem-cell based experimental therapies in neurodegenerative disorders is massively increasing. Most of the clinical trials registered to date have been based on autologous mesenchymal stem/stromal cells (MSC) obtained from somatic tissues. In the conducted clinical trials neither serious side effects, nor statistically significant improvement were observed. The lack of statistical significance could result from a relatively small number of patients involved in clinical trials or highly incoherent study protocols. However, most clinical groups describe a trend towards improvement in MSC-treated patients. Hence, the question arises which factors associated with MSC-based therapy may be the key and result in better therapeutic response. In the presented paper, we summarize, in our opinion, the most important factors that could increase the effectiveness of this therapy.

Autophagy functions as the primary cellular mechanism for clearing unwanted intracellular contents. Emerging evidence suggests that the selective elimination of intracellular organelles through autophagy, compared to the increased bulk autophagic flux, is crucial for the pathological progression of central nervous system (CNS) disorders. Notably, autophagic removal of mitochondria, known as mitophagy, is well-understood in an unhealthy brain. Accumulated data indicate that selective autophagy of other substrates, including protein aggregates, liposomes, and endoplasmic reticulum, plays distinctive roles in various pathological stages. Despite variations in substrates, the molecular mechanisms governing selective autophagy can be broadly categorized into two types: ubiquitin-dependent and -independent pathways, both of which can be subjected to regulation by small-molecule compounds. Notably, natural products provide the remarkable possibility for future structural optimization to regulate the highly selective autophagic clearance of diverse substrates. In this context, we emphasize the selectivity of autophagy in regulating CNS disorders and provide an overview of chemical compounds capable of modulating selective autophagy in these disorders, along with the underlying mechanisms. Further exploration of the functions of these compounds will in turn advance our understanding of autophagic contributions to brain disorders and illuminate precise therapeutic strategies for these diseases. [ABSTRACT FROM AUTHOR]

The present study was designed to characterize transduction of non-human primate brain and spinal cord with a modified adeno-associated virus serotype 2, incapable of binding to the heparan sulfate proteoglycan receptor, referred to as AAV2-HBKO. AAV2-HBKO was infused into the thalamus, intracerebroventricularly or via a combination of both intracerebroventricular and thalamic delivery. Thalamic injection of this modified vector encoding GFP resulted in widespread CNS transduction that included neurons in deep cortical layers, deep cerebellar nuclei, several subcortical regions, and motor neuron transduction in the spinal cord indicative of robust bidirectional axonal transport. Intracerebroventricular delivery similarly resulted in widespread cortical transduction, with one striking distinction that oligodendrocytes within superficial layers of the cortex were the primary cell type transduced. Robust motor neuron transduction was also observed in all levels of the spinal cord. The combination of thalamic and intracerebroventricular delivery resulted in transduction of oligodendrocytes in superficial cortical layers and neurons in deeper cortical layers. Several subcortical regions were also transduced. Our data demonstrate that AAV2-HBKO is a powerful vector for the potential treatment of a wide number of neurological disorders, and highlight that delivery route can significantly impact cellular tropism and pattern of CNS transduction.

Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB's integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100–300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy. [ABSTRACT FROM AUTHOR]

Back ground: In brazil, the plant Morinda citrifolia, popularly known as noni, is widely utilized in traditional medicine. Many components of the noni tree, including the roots, leaves, and seeds, are used in these traditions. Because of its high antioxidant activity and established health advantages Morinda citrifolia (Noni) has been widely utilized as a complementary and alternative medicine in many countries. The noni plant has an ancient legacy of being used to cure a range of diseases including CNS abnormalities. It has historically used as an antidepressant, anxiolytic, antiepileptic activity, antipsychotic, nootropic activity, anticraving activity aganist alcohol dependence, antiemetic activity, neuroprotective agent. Objective: Based on preclinical research published in the literature, the current study underlines noni therapeutic potential activities for the treatment of cns disorders. The literature was collected from research gate, Wikipedia, medline, scholarly articles, online databases and academic search. The present review targeted on mostly receptors, enzyme transporters and invivo, invitro and insilico methods for different cns disorders. Conclusion:The monoamine oxidase (MAO) A and B bioassays were used to evaluate the antidepressant effects of Morinda citrifolia (noni) fruit extracts invitro. Nonifruit has a synergistic impact because of its active components, involved in inhibiting MAOA and MAOB enzymes. The methanolic extract of noni shows antipsychotic activity by inhibiting dopaminergic receptors. Administration of benzodiazepine and MMC attenuated anxiolytic activityin mouse models. Noni inhibits acetycholine esterase enzyme and exhibits nootropic activity. Noni exhibits anticraving activity against alcoholdependence by CPP test. Noni exhibits neuroprotective activity by decreasing the brain damage and dysfunction caused by reperfusion injury. [ABSTRACT FROM AUTHOR]

While the drug development literature provides numerous estimates of the financial costs to bring a new drug to market, the investment of patient-participants in the research process has not been described. Trial participants and their caregivers, like companies, invest time and undertake risk when they participate in prelicense trials. We determined the average number of patient-participants needed to develop a novel neurological drug. We created a cohort of 108 unapproved drugs first tested for efficacy between 2006 and 2011 and used ClinicalTrials.gov to capture enrollment in all subsequent prelicense trials of these drugs over a 9-year period. Our primary outcome was the average number of patients enrolled in prelicense neurological drug trials per drug that ultimately attained FDA approval, including patients who participated in both successful and unsuccessful development efforts. Five drugs (4.6%) were FDA approved, and 66,751 patient-participants were enrolled across successful and unsuccessful drug development efforts, resulting in an average of 13,350 patients for each drug attaining approval (95% CI 7155 to 54,954). Our estimates reveal the substantial amount patients and their caregivers contribute to private drug development. [ABSTRACT FROM AUTHOR]

The etiologies of several cardiovascular, inflammatory, neurological, hereditary disorders, cancer, and infectious diseases have implicated changes in the genetic set up or genetic mutations as the root cause. Nucleic acid based therapeutics (NBTs) is a new class of biologics that are known to regulate gene expression at the transcriptional and post-transcriptional level. The NBTs include oligonucleotides, nucleosides, antisense RNA, small interfering RNAs, micro RNA etc. In recent times, this new category of biologics has found enormous potential in the management of cardiovascular, inflammatory, neurological disorders, cancer, infectious diseases and organ transplantation. However, the delivery of NBTs is highly challenging in terms of target specificity (intracellular delivery), mononuclear phagocyte system uptake, stability and biodistribution. Additionally, management of the above mentioned disorders require regular and intrusive therapy making non-invasive routes preferable in comparison to invasive routes like parenteral. The nasal route is garnering focus in delivery of NBTs to the brain in the management of several CNS disorders due to the associated merits such as non-invasiveness, possibility of chronic delivery, improved patient compliance, avoidance of hepatic and gastrointestinal metabolism as well as ability to bypass the BBB. Hence in recent times, this route has been sought by the reserachers as an alternative to parenteral therapy for the delivery of several NBTs. This review shall focus on an array of NBTs delivered through nasal route, their challenges, applications and opportunities. The novel delivery systems for incorporating NBTs; their targeting strategies shall be critically reviewed. The challenges towards regulatory approvals and commercialization shall also be discussed at large. Comparison of learnings derived from the success and barriers in nasal delivery of NBTs will help in identification of futuristic opportunities for their translation from bench to bedside. [ABSTRACT FROM AUTHOR]

In addition to genetic information, environmental factors play an important role in the structure and function of nervous system and the occurrence and development of some nervous system diseases. Enriched environment (EE) can not only promote normal neural development through enhancing neuroplasticity but also play a nerve repair role in restoring functional activities during CNS injury by morphological and cellular and molecular adaptations in the brain. Different stages of development after birth respond to the environment to varying degrees. Therefore, we systematically review the pro-developmental and anti-stress value of EE during pregnancy, pre- weaning, and "adolescence" and analyze the difference in the effects of EE and its sub-components, especially with physical exercise. In our exploration of potential mechanisms that promote neurodevelopment, we have found that not all sub-components exert maximum value throughout the developmental phase, such as animals that do not respond to physical activity before weaning, and that EE is not superior to its sub-components in all respects. EE affects the developing and adult brain, resulting in some neuroplastic changes in the microscopic and macroscopic anatomy, finally contributing to enhanced learning and memory capacity. These positive promoting influences are particularly prominent regarding neural repair after neurobiological disorders. Taking cerebral ischemia as an example, we analyzed the molecular mediators of EE promoting repair from various dimensions. We found that EE does not always lead to positive effects on nerve repair, such as infarct size. In view of the classic issues such as standardization and relativity of EE have been thoroughly discussed, we finally focus on analyzing the essentiality of the time window of EE action and clinical translation in order to devote to the future research direction of EE and rapid and reasonable clinical application. [ABSTRACT FROM AUTHOR]

The etiologies of several cardiovascular, inflammatory, neurological, hereditary disorders, cancer, and infectious diseases have implicated changes in the genetic set up or genetic mutations as the root cause. Nucleic acid based therapeutics (NBTs) is a new class of biologics that are known to regulate gene expression at the transcriptional and post-transcriptional level. The NBTs include oligonucleotides, nucleosides, antisense RNA, small interfering RNAs, micro RNA etc. In recent times, this new category of biologics has found enormous potential in the management of cardiovascular, inflammatory, neurological disorders, cancer, infectious diseases and organ transplantation. However, the delivery of NBTs is highly challenging in terms of target specificity (intracellular delivery), mononuclear phagocyte system uptake, stability and biodistribution. Additionally, management of the above mentioned disorders require regular and intrusive therapy making non-invasive routes preferable in comparison to invasive routes like parenteral. The nasal route is garnering focus in delivery of NBTs to the brain in the management of several CNS disorders due to the associated merits such as non-invasiveness, possibility of chronic delivery, improved patient compliance, avoidance of hepatic and gastrointestinal metabolism as well as ability to bypass the BBB. Hence in recent times, this route has been sought by the reserachers as an alternative to parenteral therapy for the delivery of several NBTs. This review shall focus on an array of NBTs delivered through nasal route, their challenges, applications and opportunities. The novel delivery systems for incorporating NBTs; their targeting strategies shall be critically reviewed. The challenges towards regulatory approvals and commercialization shall also be discussed at large. Comparison of learnings derived from the success and barriers in nasal delivery of NBTs will help in identification of futuristic opportunities for their translation from bench to bedside.

Malignant tumors and central nervous system (CNS) disorders are intricately linked to a process known as "aberrant cell cycle re-entry," which plays a critical role in the progression of these diseases. Addressing the dysregulation in cell cycles offers a promising therapeutic approach for cancers and CNS disorders. MicroRNAs (miRNAs) play a crucial role as regulators of gene expression in cell cycle transitions, presenting a promising therapeutic avenue for treating these disorders and their comorbidities. This review consolidates the progress made in the last three years regarding miRNA-based treatments for diseases associated with aberrant cell cycle re-entry. It encompasses exploring fundamental mechanisms and signaling pathways influenced by miRNAs in cancers and CNS disorders, particularly focusing on the therapeutic effects of exosome-derived miRNAs. The review also identifies specific miRNAs implicated in comorbidity of cancers and CNS disorders, discusses the future potential of miRNA reagents in managing cell cycle-related diseases. [Display omitted] • Linking miRNAs to cell cycle dysregulation in cancers and CNS disorders. • Highlighting exosome-derived miRNAs in the treatment of cancers and CNS disorders. • Revealing the shared mechanism of miRNAs-based interventions in cancers and CNS disorders. • Identifying specific miRNAs in comorbidity of cancers and CNS disorders. • Discussing the challenges of miRNA reagents in disease management. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) disorders exhibit exceedingly intricate pathogenic mechanisms. Pragmatic and effective solutions remain elusive, significantly compromising human life and health. Activating transcription factor 4 (ATF4) participates in the regulation of multiple pathophysiological processes, including CNS disorders. Considering the widespread involvement of ATF4 in the pathological process of CNS disorders, the targeted regulation of ATF4 by plant-derived bioactive compounds (PDBCs) may become a viable strategy for the treatment of CNS disorders. However, the regulatory relationship between PDBCs and ATF4 remains incompletely understood. Here, we aimed to comprehensively review the studies on PDBCs targeting ATF4 to ameliorate CNS disorders, thereby offering novel directions and insights for the treatment of CNS disorders. A computerized search was conducted on PubMed, Embase, Web of Science, and Google Scholar databases to identify preclinical experiments related to PDBCs targeting ATF4 for the treatment of CNS disorders. The search timeframe was from the inception of the databases to December 2023. Two assessors conducted searches using the keywords "ATF4," "Central Nervous System," "Neurological," "Alzheimer's disease," "Parkinson's Disease," "Stroke," "Spinal Cord Injury," "Glioblastoma," "Traumatic Brain Injury," and "Spinal Cord Injury." Overall, 31 studies were included, encompassing assessments of 27 PDBCs. Combining results from in vivo and in vitro studies, we observed that these PDBCs, via ATF4 modulation, prevent the deposition of amyloid-like fibers such as Aβ, tau, and α-synuclein. They regulate ERS, reduce the release of inflammatory factors, restore mitochondrial membrane integrity to prevent oxidative stress, regulate synaptic plasticity, modulate autophagy, and engage anti-apoptotic mechanisms. Consequently, they exert neuroprotective effects in CNS disorders. Numerous PDBCs targeting ATF4 have shown potential in facilitating the restoration of CNS functionality, thereby presenting expansive prospects for the treatment of such disorders. However, future endeavors necessitate high-quality, large-scale, and comprehensive preclinical and clinical studies to further validate this therapeutic potential. [Display omitted] • ATF4 is widely implicated in the pathological mechanisms of Central nervous system (CNS) disorders. • The studies of 27 plant-derived bioactive compounds (PDBCs) targeting ATF4 for the treatment of CNS disorders incorporated into the study. • The PDBCs exert their effects in the treatment of CNS disorders by modulating ATF4. [ABSTRACT FROM AUTHOR]

The complement system, an essential tightly regulated innate immune system, is a key regulator of normal central nervous system (CNS) development and function. However, aberrant complement component expression and activation in the brain may culminate into marked neuroinflammatory response, neurodegenerative processes and cognitive impairment. Over the years, complement‐mediated neuroinflammatory responses and complement‐driven neurodegeneration have been increasingly implicated in the pathogenesis of a wide spectrum of CNS disorders. This review describes how complement system contributes to normal brain development and function. We also discuss how pathologic insults such as misfolded proteins, lipid droplet/lipid droplet‐associated protein or glycosaminoglycan accumulation could trigger complement‐mediated neuroinflammatory responses and neurodegenerative process in neurodegenerative proteinopathies, age‐related macular degeneration and neurodegenerative lysosomal storage disorders. [ABSTRACT FROM AUTHOR]