Mitofusin 2 in central nervous system disorders: Roles in mitochondrial dynamics and therapeutic Implications.

PROTACs for central nervous system disorders: challenges and opportunities.

Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS) disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56) which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA) is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimer's disease (AD). Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic) in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1β, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death.

MicroRNAs (miRNAs) are a class of endogenous, non-coding, single-stranded RNAs with a length of approximately 22 nucleotides that are found in eukaryotes. miRNAs are involved in the regulation of cell differentiation, proliferation, invasion, apoptosis, and metabolism by regulating the expression of their target genes. Emerging studies have suggested that various miRNAs play key roles in the pathogenesis of central nervous system (CNS) disorders and may be viable therapeutic targets. In particular, miR-21 has prominently emerged as a focus of increasing research on the mechanisms of its involvement in CNS disorders. Herein, we reviewed recent studies on the critical roles of miR-21, including its dysregulated expression and target genes, in the regulation of pathophysiological processes of CNS disorders, with a special focus on apoptosis and inflammation. Collectively, miR-21 is a versatile regulator in the progression of CNS disorders and could be a promising biomarker and therapeutic target for these diseases. An in-depth understanding of the mechanisms by which miR-21 affects the pathogenesis of CNS disorders could pave the way for miR-21 to serve as a therapeutic target for these conditions.

Background Excessive sugar consumption has paralleled the global rise in obesity, type 2 diabetes mellitus (T2DM), and related metabolic disorders. High-sugar diets directly contribute to weight gain, insulin resistance, and chronic hyperglycemia, which drive cardiovascular complications and systemic inflammation through advanced glycation end products (AGEs) and oxidative stress. Emerging evidence highlights their critical role in the pathogenesis of central nervous system (CNS) disorders, including Alzheimer’s disease, Parkinson’s disease, and stroke, likely mediated through obesity-associated chronic inflammation, T2DM-driven blood-brain barrier dysfunction, and neuroinflammation. Rationale and aim of the study This review explores the impact of high-sugar diets on CNS diseases, focusing on the mechanisms involved, such as neuroinflammation, oxidative stress, insulin resistance, and altered neurotransmission. Methods: For this purpose, databases, such as PubMed, Medline, and PubMed Central (PMC) have been searched. Results Accumulating evidence underscores the detrimental impact of high-sugar diets, particularly those high in glucose and fructose, on CNS diseases. These dietary patterns are linked to the exacerbation of various CNS diseases through multiple pathways. After analyzing the current literature, we can develop targeted dietary interventions aimed at reducing the burden of CNS diseases associated with high-sugar diets. Discussion and conclusion This paper emphasizes the importance of adopting nutritional approaches that address both metabolic and neurological health to combat the growing burden of CNS diseases linked to high-sugar consumption.

Chapter 3 - Nanoengineering and nanotechnology for diagnosis and treatment of CNS and neurological diseases

Long-term non-invasive ventilation (LT-NIV) is commonly used to treat sleep-related breathing disorders (SRBD) in children. Children with central nervous system (CNS) disorders experience a high rate of SRBDs. However, the outcomes of LT-NIV use for children with CNS disorders remains unclear. This systematic review is a sub-study of a scoping review on LT-NIV use in children. The scoping review search strategy identified studies of children using LT-NIV from January 1990 to March 2024. These results were searched for studies of children with CNS disorders. To identify studies for meta-analysis, studies were grouped as: 1) studies of children with CNS disorders as part of broader a broader group of children using LT-NIV; 2) studies exclusively of children with CNS disorders using LT-NIV; and 3) studies of children with congenital central hypoventilation syndrome using LT-NIV. The Non-Randomized Studies of Interventions tool was used to assessed risk of bias. A total of 55 studies met inclusion criteria and included 2,015 children with CNS disorders using LT-NIV. Nineteen studies reported outcomes specific to children with CNS disorders. Meta-analysis of four studies showed no difference in mortality between children with and without CNS disorders(1.23, 95% CI: 0.40-3.79). Hospitalization rates across four studies suggested a higher rate of hospitalization in children with CNS disorders compared to children without CNS disorders. Meta-analysis of three studies showed reductions in the apnoea-hypopnoea index following LT-NIV use; the response to LT-NIV, however, varied across individual studies. LT-NIV use may benefit some children with CNS disorders, particularly through improvements in sleep-related breathing disorders. However, data remain limited, and uncertainty persists regarding the impact on mortality, hospitalization, and other important outcomes.

Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a book series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of central nervous system (CNS) and other nerve disorders. The scope of the book series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of contemporary molecular targets involved in neurological and CNS disorders. Reviews presented in the series are mainly focused on clinical and therapeutic aspects of novel drugs intended for these targets. Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for developing clinical trials and devising research plans in neurology and allied disciplines. The twelfth volume of this series features these reviews: Chapter 1: Recent Drugs Tested in Clinical Trials for Alzheimer's and Parkinson's Diseases Treatment: Current Approaches in Tracking New Drugs Chapter 2: Neurobiology of Placebo: Interpreting Its Evolutionary Origin, Meaning, Mechanisms, Monitoring, and Implications in Therapeutics Chapter 3: Role of Gut Microbiota in Neuroinflammation and Neurological Disorders Chapter 4: The Role of Age in Pediatric Tumors of the Central Nervous System Chapter 5: Drug Repurposing in CNS and Clinical Trials: Recent Achievements and Perspectives Focusing on Epilepsy and Related Comorbidities Chapter 6: Progress on the Development of Oxime Derivatives as a Potential Antidote for Organophosphorus Poisoning .

Neurological disorders are diverse, have complex causes, and often result in disability; yet, effective treatments remain scarce. The resveratrol derivative pterostilbene possesses numerous physiological activities that hold promise as a novel therapy for the central nervous system (CNS) disorders. This review aimed to summarize the protective mechanisms of pterostilbene in in vitro and in vivo models of CNS disorders and the pharmacokinetics and safety to assess its possible effects on CNS disorders. Available evidence supports the protective effects of pterostilbene in CNS disorders involving mechanisms such as antioxidant and anti-inflammatory activity, regulation of lipid metabolism and vascular smooth muscle cell proliferation, improvement of synaptic function and neurogenesis, induction of glioma cell cycle arrest, and inhibition of glioma cell migration and invasion. Studies have identified possible molecular targets and pathways for the protective actions of pterostilbene in CNS disorders including the AMPK/STAT3, Akt, NF-κB, MAPK, and ERK signaling pathways. The possible pharmacological effects and molecular pathways of pterostilbene in CNS disorders are critically discussed in this review. Future studies should aim to increase our understanding of pterostilbene in animal models and humans to further evaluate its role in CNS disorders and the detailed mechanisms.

Background Metronidazole (MNZ) can be administered for various infections. The impact of comorbidities/concomitant drugs on MNZ-induced central nervous system (CNS) disorders remains unclear. Research design and methods We assessed the risk of metronidazole-related CNS disorders using the Japan Adverse Drug Event Report (JADER, May 2023) and the US Food and Drug Administration Adverse Event Reporting System (FAERS, Q1 2023), excluding comorbidities/concomitant drugs. Clonazepam and diazepam were evaluated as potential prophylactics based on the efficacy of benzodiazepines for MNZ-related CNS disorders. Reporting odds ratios (ROR) and 95% confidence intervals (CI) were calculated. Additionally, sensitivity analysis by sex and age was conducted. Results The ROR (95% CI) of CNS disorders associated with MNZ in JADER and FAERS were 3.16 (2.69–3.72) and 1.69 (1.64–1.73), respectively. MNZ was significantly related to CNS disorders after excluding comorbidities (brain/spinal cord or liver abscesses) and concomitant drugs (glucocorticoids, antiepileptic, antiparkinson, and schizophrenia drugs). In sensitivity analysis, MNZ was significantly related to CNS disorders, despite sex and age. The ROR in the concomitant with clonazepam (CZP) was 0.70 (0.53–0.92) in FAERS. Conclusion MNZ may be associated with CNS disorders, even if comorbidities/concomitant drugs that are potential risk factors for CNS disorders are excluded. Additionally, CZP may suppress CNS disorders.

Central nervous system (CNS) disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and migraines, rank among the most prevalent and concerning conditions worldwide. Despite ongoing research, the pathophysiology of these disorders remains incompletely understood, primarily due to their complex etiology. Current pharmacological treatments mainly focus on alleviating symptoms rather than addressing the underlying causes of these diseases. CNS disorders are marked by impairments in neurocognitive and neuromuscular functions, and cognitive processes like learning and memory. This deterioration not only impacts the quality of life of affected individuals but also places a significant burden on their families. Neuroplasticity is a key property of the nervous system that enables brain repair and functional recovery. However, in CNS disorders, neuroplasticity is often compromised. Neuroplasticity, which is regulated by gene expression, is also modulated by environmental factors and epigenetic mechanisms, thereby reshaping neuronal networks in response to various biological and environmental stimuli and brain function. Importantly, neuroplasticity plays a critical role in repairing the brain, especially in the context of neurodegenerative diseases, where damaged neurons can reorganize and re-establish lost functions. Targeting neuroplasticity mechanisms holds significant potential for developing therapeutic interventions to improve treatment outcomes and prevent CNS disorders. A deeper understanding of neuroplasticity in neurological diseases could open new avenues for enhancing patient quality of life. This review aims to provide a comprehensive overview of synaptic function and the neuroplasticity mechanisms that are disrupted in neurological disorders.

Neuropharmacological insights into Gardenia jasminoides Ellis: Harnessing therapeutic potential for central nervous system disorders

The immune-to-brain communication is still in its infancy but there is a great deal of data to suggest its importance in several central nervous system (CNS) disorders. There are three cytokines, interleukin-1 (IL-1), IL-6 and tumor necrosis factor alpha (TNFα), which have emerged to have a major role in the CNS and in different CNS disorders. The majority of the published work to date has been on examining changes in the levels of these proteins in the CNS with inflammation; but recent work from our laboratory has shown the receptors for these cytokines may also be an important factor in neuroinflammation mediated CNS disorders, because these receptors are solely localized to neurons and are modified when their ligands levels are elevated. For neuroinflammation and the increase in cytokine levels (either by glia or neurons) to influence neurons and consequently affect the development of CNS disorders, the location of these cytokines receptors on neuronal populations may be the key.

Bone-brain crosstalk: emerging roles of osteocalcin in central nervous system disorders.

Copper (Cu), an indispensable micronutrient for the sustenance of living organisms, contributes significantly to a vast array of fundamental metabolic processes. The human body maintains a relatively low concentration of copper, which is mostly found in the bones, liver, and brain. Despite its low concentration, Cu plays a crucial role as an indispensable element in the progression and pathogenesis of central nervous system (CNS) diseases. Extensive studies have been conducted in recent years on copper homeostasis and copper-induced cell death in CNS disorders, including glioma, Alzheimer’s disease, Amyotrophic lateral sclerosis, Huntington’s disease, and stroke. Cuproptosis, a novel copper-induced cell death pathway distinct from apoptosis, necrosis, pyroptosis, and ferroptosis, has been identified as potentially intricately linked to the pathogenic mechanisms underlying various CNS diseases. Therefore, a systematic review of copper homeostasis and cuproptosis and their relationship with CNS disorders could deepen our understanding of the pathogenesis of these diseases. In addition, it may provide new insights and strategies for the treatment of CNS disorders.

Cardiolipin (CL), a unique dimeric phospholipid predominantly enriched in the inner mitochondrial membrane, is a crucial determinant of mitochondrial structure and function. Its content, fatty acyl composition, and oxidation state are associated with mitochondrial bioenergetics, dynamics, and cellular signaling. Disruptions in CL metabolism are increasingly implicated in the pathogenesis of various central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and traumatic brain injury. This narrative review summarizes recent advances in the analytical techniques employed for CL analysis. The principles and applications of mass spectrometry-based platforms, nuclear magnetic resonance, Fourier-transform infrared spectroscopy, atomic force microscopy-infrared spectroscopy, and fluorescent probes were discussed, with an emphasis on their strengths in revealing the structure, composition, dynamics, and spatial distribution of CL. Furthermore, the evidence of CL abnormalities in various CNS disorders was assessed, often showing decreased CL levels, loss of polyunsaturated species, and increased oxidation associated with mitochondrial dysfunction and neuronal apoptosis. Furthermore, the nutritional interventions for CL modulation were discussed, such as polyunsaturated fatty acids, polyphenols, carotenoids, retinoids, alkaloids, and triterpenoids, which summarize their potential health-beneficial effects in remodeling the CL acyl chain, preventing oxidation, and regulating mitochondrial homeostasis. Overall, this review provided insight into integrating CL analysis and dietary modulation in understanding CL-related pathologies in CNS disorders.