CNS & neurological disorders drug targets最新文献

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder determined by a combination of both genetic and environmental factors. Despite wide investigations, the role of chronic exposure to environmental pollutants is still rather unknown. Among natural toxins, the mycotoxins have received major attention only in the last few years, due to both technical and scientific achievements that allowed to disentangle many important features of the complex fungal biology. Whereas the effects of acute and high-dose mycotoxin exposure are well known, the potential effects of chronic and low-dose exposure on neurodegeneration have not been broadly elucidated. In this review, we have summarized all the studies concerning environmental exposure to unknown substances that caused ALS outbreaks all over the world, reinterpreting in light of the new scientific acquisitions and highlighting the potential and neglected role of mycotoxins. Then, we focused on recent papers about food exposure to mycotoxin, mycobiome and fungal infections in ALS and other neurodegenerative diseases. We analyzed the gaps of current literature that lead to an undervaluation of mycotoxins as detrimental molecules. By listing all the most important mycotoxins and analyzing all the biological pathways that they can affect, we explained the reasons why they need to be considered in the next epidemiological studies on ALS and other neurodegenerative and neuroinflammatory diseases. In conclusion, after suggesting some possible solutions to mitigate mycotoxin exposure risk, we affirm that future collaborations between scientists and policymakers are important to develop sustainable interventions and promote health through dietary diversity.

Hypovolemic shock (HS), a clinical condition of insufficient blood perfusion and oxygenation in body tissues, is associated with immense morbidity and mortality. Treatment approaches include fluid replacement and surgical repair of reversible causes of hemorrhage; however, they cause irreversible blood perfusion loss, systemic inflammation, multiple organ failure, and death. Centhaquin citrate (CC) is an innovative centrally acting cardiovascular active agent that is initially intended as an antihypertensive drug. However, due to its positive ionotropic effect, Centhaquin citrate is being tested clinically as a resuscitative agent for the management of hypovolemic shock It acts at the α2B-adrenergic receptor to produce venous constriction followed by an increase in venous return to the heart. These actions are assumed to be capable of resuscitative activity observed by centhaquin citrate, through an increase in cardiac output and tissue perfusion. Pharmacokinetics investigations in animals and humans have shown that centhaquin citrate is well tolerated and has insignificant side effects. Therefore, centhaquin citrate seems to be a promising entity and gaining the interest of researchers to develop it as a resuscitative agent in HS. The review gives insight into the development of centhaquin citrate as a resuscitative agent and provides insight into the associated mechanism of action and molecular signalling to foster future research on CC for its clinical use in HS.

The blood-brain barrier (BBB) plays a crucial role in the central nervous system by tightly regulating the influx and efflux of biological substances between the brain parenchyma and peripheral circulation. Its restrictive nature acts as an obstacle to protect the brain from potentially noxious substances such as blood-borne toxins, immune cells, and pathogens. Thus, the maintenance of its structural and functional integrity is vital in the preservation of neuronal function and cellular homeostasis in the brain microenvironment. However, the barrier's foundation can become compromised during neurological or pathological conditions, which can result in dysregulated ionic homeostasis, impaired transport of nutrients, and accumulation of neurotoxins that eventually lead to irreversible neuronal loss. Initially, the BBB is thought to remain intact during neurodegenerative diseases, but accumulating evidence as of late has suggested the possible association of BBB dysfunction with Parkinson's disease (PD) pathology. The neurodegeneration occurring in PD is believed to stem from a myriad of pathogenic mechanisms, including tight junction alterations, abnormal angiogenesis, and dysfunctional BBB transporter mechanism, which ultimately causes altered BBB permeability. In this review, the major elements of the neurovascular unit (NVU) comprising the BBB are discussed, along with their role in the maintenance of barrier integrity and PD pathogenesis. We also elaborated on how the neuroendocrine system can influence the regulation of BBB function and PD pathogenesis. Several novel therapeutic approaches targeting the NVU components are explored to provide a fresh outlook on treatment options for PD.

The burden of neurological illnesses on global health is significant. Our perception of the molecular and biological mechanisms underlying intellectual processing and behavior has significantly advanced over the last few decades, laying the groundwork for potential therapies for various neurodegenerative diseases. A growing body of literature reveals that most neurodegenerative diseases could be due to the gradual failure of neurons in the brain's neocortex, hippocampus, and various subcortical areas. Research on various experimental models has uncovered several gene components to understand the pathogenesis of neurodegenerative disorders. One among them is the brain-derived neurotrophic factor (BDNF), which performs several vital functions, enhancing synaptic plasticity and assisting in the emergence of long-term thoughts. The pathophysiology of some neurodegenerative diseases, including Alzheimer's, Parkinson's, Schizophrenia, and Huntington's, has been linked to BDNF. According to numerous research, high levels of BDNF are connected to a lower risk of developing a neurodegenerative disease. As a result, we want to concentrate on BDNF in this article and outline its protective role against neurological disorders.

Background: Existing therapeutic alternatives for neonatal crises have expanded in recent decades, but no consensus has been reached on protocols based on neonatal seizures. In particular, little is known about the use of midazolam in newborns.

Aim: The aim of our study is to evaluate the response to midazolam, the appearance of side effects, and their impact on therapeutic decisions.

Methods: This is a STROBE-conformed retrospective observational study of 10 patients with neonatal seizures unresponsive to common antiseizure drugs, admitted to San Marco University Hospital's neonatal intensive care (Catania, Italy) from September 2015 to October 2022. In our database search, 36 newborns were treated with midazolam, but only ten children met the selection criteria for this study.

Results: Response was assessed both clinically and electrographic. Only 4 patients at the end of the treatment showed a complete electroclinical response; they were full-term infants with a postnatal age greater than 7 days. Non-responders and partial responders are all premature (4/10) or full-term neonates who started therapy in the first days of life (< 7th day) (2/10).

Conclusion: Neonatal seizures in preterm show a lower response rate to midazolam than seizures in full-term infants, with poorer prognosis. Liver and renal function and central nervous system development are incomplete in premature infants and the first days of life. In this study, we show that midazolam, a short-acting benzodiazepine, appears to be most effective in full-term infants and after 7 days of life.

Lorcaserin is a 3-benzazepine that binds 5-HT_2C serotonin receptors in the hypothalamus, where it mediates lack of hunger and/or satiety, and in the ventral tegmental area, the site of origin of the mesolimbic and mesocortical dopaminergic projections, which mediate pleasure and reward. The drug has been first developed for the treatment of obesity, where it has shown efficacy, and subsequently trialed to counter substance use (mostly cocaine, cannabis, opioids, and nicotine) and craving, but showed inconsistent effects. Since 2020, the US Food and Drug Administration obtained that the drug was voluntarily withdrawn from the US market on the grounds that its long-term use was found to be associated with a greater incidence of some types of cancer. Provided it can show to be free from cancerogenic effects, ongoing research suggests that lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Since 5-HT_2C receptors are involved in many diversified physiological functions (mood, feeding, reproductive behavior, neuronal processes related to impulsiveness, and modulating reward-related mechanisms) this drug has the potential to treat different central nervous system conditions, such as depression and schizophrenia.

Background: Bibliometric analysis allows us to quantify and evaluate scientific activity, and it has become increasingly important in all areas of scientific literature. Thanks to these analyses, we can infer where science should put greater efforts into elucidating the underlying mechanisms of diseases that have yet to be fully described or investigated.

Objective: This paper delves into published articles related to the involvement of calcium (Ca²⁺) channels in epilepsy, which is a condition with a high prevalence in Latin America.

Methods: We followed the scientific publication on SCOPUS and analyzed the impact of publications from Latin America in the field of epilepsy and the study of Ca²⁺ channels. We identified the countries with the largest number of publications and found that 68% of them were experimental (animal models), while 32% were clinical. We also identified the main journals, growth over time, and citation numbers.

Results: We found a total of 226 works produced by Latin American countries from 1976 to 2022. The countries that have contributed the most to the topic are Brazil, Mexico, and Argentina, with occasional collaborations between them to make contributions to the study of epilepsy and Ca²⁺ channels. Additionally, we found that the journal with the most citations is Nature Genetics.

Conclusion: The number of authors per article ranges from 1 to 242, and neuroscience journals are the preferred target for researchers, with a predilection for publishing original articles, although 26% of the publications are review articles.

Bell palsy is a non-progressive neurological condition characterized by the acute onset of ipsilateral seventh cranial nerve paralysis. People who suffer from this type of facial paralysis develop a droop on one side of their face, or sometimes both. This condition is distinguished by a sudden onset of facial paralysis accompanied by clinical features such as mild fever, postauricular pain, dysgeusia, hyperacusis, facial changes, and drooling or dry eyes. Epidemiological evidence suggests that 15 to 23 people per 100,000 are affected each year, with a recurrence rate of 12%. It could be caused by ischaemic compression of the seventh cranial nerve, which could be caused by viral inflammation. Pregnant women, people with diabetes, and people with respiratory infections are more likely to have facial paralysis than the general population. Immune, viral, and ischemic pathways are all thought to play a role in the development of Bell paralysis, but the exact cause is unknown. However, there is evidence that Bell's hereditary proclivity to cause paralysis is a public health issue that has a greater impact on patients and their families. Delay or untreated Bell paralysis may contribute to an increased risk of facial impairment, as well as a negative impact on the patient's quality of life. For management, antiviral agents such as acyclovir and valacyclovir, and steroid treatment are recommended. Thus, early diagnosis accompanied by treatment of the uncertain etiology of the disorder is crucial. This paper reviews mechanistic approaches, and emerging medical perspectives on recent developments that encounter Bell palsy disorder.

Parkinson's disease is the second most common neurodegenerative disease. Mitochondrial dysfunction has been associated with neurodegeneration in Parkinson's disease, and several treatments targeting mitochondria have been tested in these patients to delay disease progression and tackle disease symptoms. Herein, we review available data from randomised, double-blind clinical studies that have investigated the role of compounds targeting mitochondria in idiopathic Parkinson's disease patients, with a view of providing patients and clinicians with a comprehensive and practical paper that can inform therapeutic interventions in this group of people. A total of 9 compounds have been tested in randomized clinical trials, but only exenatide has shown some promising neuroprotective and symptomatic effects. However, whether this evidence can be translated into daily clinical practice still needs to be confirmed. In conclusion, targeting mitochondrial dysfunction in Parkinson's disease is a promising therapeutic approach, although only one compound has shown a positive effect on Parkinson's disease progression and symptoms. New compounds have been investigated in animal models, and their efficacy needs to be confirmed in humans through robust, randomised, double-blind clinical trials.

Epilepsy is one of the most common and devastating neurological disorders that causes unprovoked, recurrent seizures arising from excessive synchronized neuronal discharging. Although antiepileptic drugs (AEDs) reduce the frequency of epilepsy seizures, drug-refractory epileptic patients exert resistance to AEDs, resulting in treatment difficulty. Moreover, pharmacological treatments do not show satisfactory results in response to photosensitive epilepsy. In the recent era, light therapy emerged as a potential non-pharmacological approach for treating various diseases, including depression, seasonal affective disorders, migraine, pain, and others. Several studies have also shown the potential of light therapy in treating epilepsy. In addition, Red light evokes epilepsy seizures. Blue lenses filter the red light and significantly suppress the frequency of epilepsy seizures. However, the effects of green light on the frequency of epileptic seizures are not studied yet. In addition, light-activated gene therapy or optogenetics also emerged as a possible option for epilepsy treatment. Animal models have shown the therapeutic possibilities of optogenetics and light therapy; however, human studies addressing this possibility are still vague. This review provides the beneficial effects of light in reducing seizure frequency in epilepsy patients. A limited number of studies have been reported so far; therefore, light therapy for treating epilepsy requires more studies on animal models to provide precise results of light effects on seizures.