CNS & neurological disorders drug targets最新文献

Neurodegenerative diseases are caused by the loss of neurons and/or their myelin sheaths, which deteriorate over time and become dysfunctional. Alzheimer's disease, Parkinson's disease, and multiple sclerosis are among the most prominent neurodegenerative diseases that affect millions of older adults worldwide. Despite extensive research over several decades, controversies still surround the etiology of neurodegenerative diseases, and many of them remain incurable. Meanwhile, an increasing number of new mechanistic studies related to the microbiota-gut-brain axis have emerged, among which the relationship between the function of the intestinal barrier and neurodegenerative diseases has received widespread attention. As one of the first lines of defense between the body and the external environment, the impaired function of the intestinal barrier is closely related to the development of neurodegenerative pathologies. Among them, the microbiota-gut-brain axis disorder characterized by intestinal barrier disruption mainly includes impaired function of the intestinal microbial barrier, chemical barrier, mechanical barrier, and immune barrier. This review focuses on the structure and molecular mechanisms of the various layers of the intestinal barrier as well as their relationship with neurodegenerative lesions. In recent years, intestinal barrier repair therapies have provided new ideas for the studied disease treatment modalities. We believe that a better understanding of the role of the intestinal barrier in neurodegenerative diseases would provide new insights for the development of viable therapeutic strategies for patients.

Background: Poor-grade aneurysmal subarachnoid hemorrhage (aSAH) has been associated with severe morbidity and high mortality. It has been demonstrated that early intervention is of paramount importance. The aim of our study is to evaluate the functional outcome and the overall survival of early microsurgically treated patients.

Material and methods: Poor-grade aSAH patients admitted at our institution over fifteen years (January 2008 - December 2022) were included in our retrospective study. All participants underwent brain Computed Tomography Angiography (CTA). Fisher scale was used to assess the severity of hemorrhage. All our study participants underwent microsurgical clipping, and their functional outcome was assessed with the Glasgow Outcome Scale (GOS). We used logistic regression analysis to identify any parameters associated with a favorable outcome at 12 months. Cox proportional hazard analysis was also performed, identifying factors affecting the length of survival.

Results: Our study included 39 patients with a mean age of 54 years. Thirty of our participants (76.9%) were Hunt and Hess grade V, while the vast majority (94.9%) were Fisher grade 4. The observed six-month mortality rate was 48.6%. The mean follow-up time was 18.6 months. The functional outcome at six months was favorable in 6 patients (16.2%), increased to 23.5% at 12 months. Our data analysis showed that the age, as well as the employment of temporary clipping during surgery, affected the overall outcome.

Conclusion: Management of poor-grade aSAH patients has been dramatically changed. Microsurgical clipping provides promising results in carefully selected younger patients.

Depression is among the main causes of disability, and its protracted manifestations could make it even harder to treat metabolic diseases. Obesity is linked to episodes of depression, which is closely correlated to abdominal adiposity and impaired food quality. The present review is aimed at studying possible links between obesity and depression along with targets to disrupt it. Research output in Pubmed and Scopus were referred for writing this manuscript. Obesity and depression are related, with the greater propensity of depressed people to gain weight, resulting in poor dietary decisions and a sedentary lifestyle. Adipokines, which include adiponectin, resistin, and leptin are secretory products of the adipose tissue. These adipokines are now being studied to learn more about the connection underlying obesity and depression. Ghrelin, a gut hormone, controls both obesity and depression. Additionally, elevated ghrelin levels result in anxiolytic and antidepressant-like effects. The gut microbiota influences the metabolic functionalities of a person, like caloric processing from indigestible nutritional compounds and storage in fatty tissue, that exposes an individual to obesity, and gut microorganisms might connect to the CNS through interconnecting pathways, including neurological, endocrine, and immunological signalling systems. The alteration of brain activity caused by gut bacteria has been related to depressive episodes. Monoamines, including dopamine, serotonin, and norepinephrine, have been widely believed to have a function in emotions and appetite control. Emotional signals stimulate arcuate neurons in the hypothalamus that are directly implicated in mood regulation and eating. The peptide hormone GLP-1(glucagon-like peptide- 1) seems to have a beneficial role as a medical regulator of defective neuroinflammation, neurogenesis, synaptic dysfunction, and neurotransmitter secretion discrepancy in the depressive brain. The gut microbiota might have its action in mood and cognition regulation, in addition to its traditional involvement in GI function regulation. This review addressed the concept that obesity-related low-grade mild inflammation in the brain contributes to chronic depression and cognitive impairments.

Background: Neurotrophins are essential factors for neural growth and function; they play a crucial role in neurodegenerative diseases where their expression levels are altered. Our previous research has demonstrated changes in synaptic plasticity and neurotrophin expression levels in a pharmacological model of Huntington's disease (HD) induced by 3-nitropropionic acid (3-NP). In the 3-NP-induced HD model, corticostriatal Long Term Depression (LTD) was impaired, but neurotrophin- 3 (NT-3) restored striatal LTD. This study delves into the NT-3-induced signaling pathways involved in modulating and restoring striatal synaptic plasticity in cerebral slices from 3-NPinduced striatal degeneration in mice in vivo.

Methods: Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways.

Results: Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT-3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery.

Conclusion: Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions.

Background: After Alzheimer's disease, the second slot for the most common neurodegenerative disease, is occupied by Parkinson's disease. The symptoms of Parkinson's are classified as motor symptoms and non-motor symptoms. Motor symptoms involve rigidity, tremors, bradykinesia, and postural instability. Non-motor symptoms consist of cognitive dysfunction, salivation, lacrimation, etc. Objectives: The objectives of this study are to find out the most recent treatment options for Parkinson's disease.

Methods: Research and review papers are collected from different databases like Google Scholar, PubMed, Mendeley, Scopus, Science Open, and the Directory of Open Access Journals using different keywords such as "Parkinson's disease, biomarkers, animal models".

Results: Currently, various novel therapeutics have been emerging for PD. These may include treatments that may control the symptoms without causing any other severe side effects with already available treatments. Better therapies such as gene therapies, cell-based treatments, and regenerative therapies, which may evolve over time, can be a better therapeutic option.

Conclusion: There is a need for the development of novel and potential therapeutic strategies that offer fewer side effects to patients. Several clinical, biochemical, and imaging markers that are noteworthy in Parkinson's disease examination have been discussed here. Current work in the field of Parkinson's disease has developed a variety of significant small animal models, such as viral vector models and seeding models, including the insertion of preformed fibrils of alpha-synuclein. The brief concepts regarding risk factors, pathogenesis, clinical diagnosis, and emerging treatments of PD are discussed in this review article.

Muscle skeletal striated cells secrete a wide range of proteins called myokines or "exerkines", which in turn perform autocrine, paracrine, or endocrine functions. For being able to act in the communication between skeletal muscle, adipose tissue, and mainly the brain, exerkines play a prominent role and potential influence on health promotion. Furthermore, we detected in the literature that one of these potential therapeutic substances derived from muscle contraction is a molecule derived from glycolytic metabolism that in the past was largely marginalized, the lactate. Currently, studies are dedicated to examining the target structures for exerkines that may contribute to the maintenance and restoration of mental health. Thus, lactate appears to be recognized as a critical mediator of exercise-related changes and their health benefits, particularly in their role in communication and coordination between organs. It is inferred that the BDNF expression mechanism can be induced by lactate, which in turn derives from the activation of SIRT pathways 1 and 2 and activates the PGC1-α cascade. The behavior of lactate concentration is intensity-dependent, directly related to the type of fast-twitch fibers (type IIb) and the recruitment of these fibers would potentiate the responses in the brain. In this sense, high-intensity exercise would establish itself as an important strategy to be considered. Despite this understanding, there is still much to be done. However, lactate appears to be a highly promising exerkine for future research initiatives and a potential biomarker to reduce illness and promote mental health.

Recently, Parkinson's disease (PD) has become a remarkable burden on families and society with an acceleration of population aging having several pathological hallmarks such as dopaminergic neuronal loss of the substantia nigra pars compacta, α-synucleinopathy, neuroinflammation, autophagy, last but not the least astrogliosis. Astrocyte, star-shaped glial cells perform notable physiological functions in the brain through several molecular and cellular mechanisms including nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. It has been well established that the downregulation of the astrocytic Nrf2 signaling pathway plays a crucial role in the pathogenesis of PD because it is a master regulator of cellular defense mechanism along with a regulator of numerous detoxifying and antioxidant enzymes gene expression. Fascinatingly, upregulation of the astrocytic Nrf2 signaling pathway attenuates the degeneration of nigrostriatal neurons, restores neuronal proliferation, rejuvenates astrocytic functions, and exhibits neuroprotective effects via numerous cellular and molecular mechanisms in the PD-like brain of the experimental animal. Here, we discuss the numerous in-vitro and in-vivo studies that evaluate the neuroprotective potential of the astrocytic Nrf2 signaling pathway against experimentally-induced PD-like manifestation. In conclusion, based on available preclinical reports, it can be assumed that the astrocytic Nrf2 signaling pathway could be an alternative target in the drug discovery process for the prevention, management, and treatment of PD.

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) is a type of non-traumatic SAH that can have detrimental effects on the central nervous system, resulting in severe disability or death.

Methods: Early nimodipine is currently the only strongly recommended pharmacological treatment that has shown efficacy in improving neurological/functional outcomes in aSAH patients. Whether statin treatment is of benefit to aSAH patients is an issue that has generated considerable interest and debate. In the present scoping review, we mapped and analyzed the available literature on metaanalyses of randomized clinical trials (RCTs) examining the effect of statins on aSAH. Seventeen meta-analyses of RCTs, published between 2008 and 2023, were identified.

Results: Treatments in included meta-analyses were based on various regimens of simvastatin, pravastatin, pitavastatin or atorvastatin for up to 21 days. Eleven of the included reports indicated some beneficial effect of statin treatment, reducing rates of at least one of the following: cerebral vasospasm, delayed cerebral ischemia/delayed ischemic neurologic deficit, mortality or functional/ neurological outcome. In contrast, six meta-analyses, showed no such effects.

Conclusion: The limitations reported by several meta-analyses, included low patient numbers or disproportionate representation of patients from certain RCTs, differences in drug treatment, patient diagnostic criteria and outcome evaluation between RCTs, as well as poor data quality or lack of RCTs data. Knowledge of the reported limitations may aid the design of future clinical trials and/or their meta-analyses.

Background: Recently, US Food and Drug Administration (FDA) has approved calcitonin gene-related peptide receptor antagonists (rimegepant, and ubrogepant), and selective serotonin receptor agonists (lasmiditan) in the management of migraine. However, the exact safety and efficacy profile of these drugs is unclear so far.

Methods: The study's primary objective was to determine the exact safety and efficacy profile. The overall estimate was calculated in terms of risk ratios using a suitable model. The subgroup analysis was also performed to check the effect of individual drugs on the outcome, whereas sensitivity analysis was performed to check the effects of outliers on the outcome. All the analyses were performed using Rev Man 5. The drugs have shown significant improvement in efficacy parameters (pain freedom, most bothersome symptoms, phonophobia, nausea, and photophobia).

Results: The subgroup analysis results have shown significant improvement in all efficacy parameters in the rimegepant and ubrogepant groups. The effect of ubrogepant on safety parameters was found to be non-significant, indicating a better safety profile of ubrogepant than lasmiditan.

Conclusion: The sensitivity analysis results have shown no effect of outliers on the efficacy parameters. Based on the available evidence, recently approved drugs are effective in the treatment of migraine, however, associated with few adverse drug reactions.

Major depressive disorder (MDD) is a complex mood disorder. While much progress has been made in understanding the pathophysiology of MDD, no single mechanism can explain all facets of this disorder. Several studies show that disturbances in biological rhythms can lead to the development of MDD. Indeed, insomnia or hypersomnia are symptoms included in the MDD diagnostic criteria. Clinical studies and meta-analyses showed a strong relationship between MDD and sleep disorders. Sleep disorder and MDD are associated with activation in the hypothalamicpituitary- adrenal (HPA) axis and inflammation. The increase in inflammatory response can activate the kynurenine pathway, decrease serotonin synthesis, and affect other factors involved in the pathophysiology of neuropsychiatric conditions. Moreover, sleep disorders and MDD can change the gut microbiota and alter the microbiota-gut-brain axis. Thus, this review discusses the relationship between MDD, circadian rhythms, and sleep disorders, describing the potential pathophysiological mechanism shared in these conditions. In addition, therapeutic opportunities based on antiinflammatory, antioxidant, HPA axis regulatory, and synapse-modulating actions are raised. For the article search, we used the PubMed database. Both sleep disorders and changes in biological rhythms have a bidirectional relationship with MDD. Although some pathophysiological mechanisms, including inflammation, changes in the gut microbiota, and decreased neuroplasticity, may be involved in the relationship between sleep, circadian rhythms, and MDD, other mechanisms are not yet well understood. Therapeutic opportunities based on anti-inflammatory, antioxidant, HPA regulatory axis, and synapse modulating actions appear to be promising targets in preventing MDD, circadian rhythm disturbances, and sleep disorders.