CNS & neurological disorders drug targets最新文献

Background: B7H3 is a co-stimulatory molecule for immune reactions found on the surface of tumor cells in a wide variety of tumors. Preclinical and clinical studies have reported it as a tumor target towards which various immunotherapy modalities could be directed. So far, good results have been obtained in hematological neoplasms; however, a contrasting situation is evident in solid tumors, including those of the CNS, which show high refractoriness to current treatments. The appearance of cellular immunotherapies has transformed oncology due to the reinforcement of the immune response that is compromised in people with cancer.

Objective: This article aims to review the literature to describe the advancement in knowledge on B7H3 as a target of CAR-T cells in pediatric gliomas to consider them as an alternative in the treatment of these patients.

Results: Although B7H3 is considered a suitable candidate as a target agent for various immunotherapy techniques, there are still limitations in using CAR-T cells to achieve the desired success.

Conclusion: Results obtained with CAR-T cells can be further improved by the suggested proposals; therefore, more clinical trials are needed to study this new therapy in children with gliomas.

Long non-coding RNAs (IncRNAs) are regulatory RNA transcripts that have recently been associated with the onset of many neurodegenerative illnesses, including Alzheimer's disease (AD). Several IncRNAs have been found to be associated with AD pathophysiology, each with a distinct mechanism. In this review, we focused on the role of IncRNAs in the pathogenesis of AD and their potential as novel biomarkers and therapeutic targets. Searching for relevant articles was done using the PubMed and Cochrane library databases. Studies had to be published in full text in English in order to be considered. Some IncRNAs were found to be upregulated, while others were downregulated. Dysregulation of IncRNAs expression may contribute to AD pathogenesis. Their effects manifest as the synthesis of beta-amyloid (Aβ) plaques increases, thereby altering neuronal plasticity, inducing inflammation, and promoting apoptosis. Despite the need for more investigations, IncRNAs could potentially increase the sensitivity of early detection of AD. Until now, there has been no effective treatment for AD. Hence, InRNAs are promising molecules and may serve as potential therapeutic targets. Although several dysregulated AD-associated lncRNAs have been discovered, the functional characterization of most lncRNAs is still lacking.

Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions worldwide. One of the leading hypotheses for the underlying cause of AD is a reduction in nicotinic receptor levels in the brain. Among the nicotinic receptors, the alpha-7-nicotinic acetylcholine receptor (α7nAChR) has received particular attention due to its involvement in cognitive function.α7nAChR is a ligand-gated ion channel that is primarily found in the hippocampus and prefrontal cortex, areas of the brain responsible for learning, memory, and attention. Studies have shown that α7nAChR dysfunction is a key contributor to the pathogenesis of AD. The receptor is involved in regulating amyloidbeta (Aβ) production, a hallmark of AD pathology. Many drugs have been investigated as α7nAChR agonists or allosteric modulators to improve cognitive deficits in AD. Clinical studies have shown promising results with α7nAChR agonists, including improved memory and cognitive function. Although several studies have shown the significance of the α7 nAChR in AD, little is known about its function in AD pathogenesis. As a result, in this review, we have outlined the basic information of the α7 nAChR's structure, functions, cellular responses to its activation, and its role in AD's pathogenesis.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, the main pathological hallmark of which is the loss of neurons, resulting in cognitive and memory impairments. Sporadic late-onset AD is a prevalent form of the disease and the apolipoprotein E4 (APOE4) genotype is the strongest predictor of the disease development. The structural variations of APOE isoforms affect their roles in synaptic maintenance, lipid trafficking, energy metabolism, inflammatory response, and BBB integrity. In the context of AD, APOE isoforms variously control the key pathological elements of the disease, including Aβ plaque formation, tau aggregation, and neuroinflammation. Taking into consideration the limited number of therapy choices that can alleviate symptoms and have little impact on the AD etiology and progression to date, the precise research strategies guided by apolipoprotein E (APOE) polymorphisms are required to assess the potential risk of age-related cognitive decline in people carrying APOE4 genotype. In this review, we summarize the evidence implicating the significance of APOE isoforms on brain functions in health and pathology with the aim to identify the possible targets that should be addressed to prevent AD manifestation in individuals with the APOE4 genotype and to explore proper treatment strategies.

Nanotechnology is a great choice for medical research, and the green synthesis approach is a novel and better way to synthesize nanoparticles. Biological sources are cost-effective, environmentally friendly, and allow large-scale production of nanoparticles. Naturally obtained 3 β-hydroxy-urs- 12-en-28-oic acids reported for neuroprotective and dendritic structure are reported as solubility enhancers. Plants are free from toxic substances and act as natural capping agents. In this review, the pharmacological properties of ursolic acid (UA) and the structural properties of the dendritic structure are discussed. UA acid appears to have negligible toxicity and immunogenicity, as well as favorable biodistribution, according to the current study, and the dendritic structure improves drug solubility, prevents drug degradation, increases circulation time, and potentially targets by using different pathways with different routes of administration. Nanotechnology is a field in which materials are synthesized at the nanoscale. Nanotechnology could be the next frontier of humankind's technological advancement. Richard Feynman first used the term 'Nanotechnology' in his lecture, "There is Plenty of Room at the Bottom", on 29th December, 1959, and since then, interest has increased in the research on nanoparticles. Nanotechnology is capable of helping humanity by solving major challenges, particularly in neurological disorders like Alzheimer's disease (AD), the most prevalent type, which may account for 60-70% of cases. Other significant forms of dementia include vascular dementia, dementia with Lewy bodies (abnormal protein aggregates that form inside nerve cells), and a number of illnesses that exacerbate frontotemporal dementia. Dementia is an acquired loss of cognition in several cognitive domains that are severe enough to interfere with social or professional functioning. However, dementia frequently co-occurs with other neuropathologies, typically AD with cerebrovascular dysfunction. Clinical presentations show that neurodegenerative diseases are often incurable because patients permanently lose some neurons. A growing body of research suggests that they also advance our knowledge of the processes that are probably crucial for maintaining the health and functionality of the brain. Serious neurological impairment and neuronal death are the main features of neurodegenerative illnesses, which are also extremely crippling ailments. The most prevalent neurodegenerative disorders cause cognitive impairment and dementia, and as average life expectancy rises globally, their effects become more noticeable.

Neurocognitive disorders associated with human immunodeficiency virus (HIV) infected individuals increase the risk of mortality and morbidity that remain a prevalent clinical complication even in the antiretroviral therapy era. It is estimated that a considerable number of people in the HIV community are developing neurological complications at their early stages of infection. The daily lives of people with chronic HIV infections are greatly affected by cognitive declines such as loss of attention, learning, and executive functions, and other adverse conditions like neuronal injury and dementia. It has been found that the entry of HIV into the brain and subsequently crossing the blood-brain barrier (BBB) causes brain cell damage, which is the prerequisite for the development of neurocognitive disorders. Besides the HIV replication in the central nervous system and the adverse effects of antiretroviral therapy on the BBB, a range of opportunistic infections, including viral, bacterial, and parasitic agents, augment the neurological complications in people living with HIV (PLHIV). Given the immuno-compromised state of PLHIV, these co-infections can present a wide range of clinical syndromes with atypical manifestations that pose challenges in diagnosis and clinical management, representing a substantial burden for the public health system. Therefore, the present review narrates the neurological complications triggered by HIV and their diagnosis and treatment options. Moreover, coinfections that are known to cause neurological disorders in HIV infected individuals are highlighted.

Background: Autism Spectrum Disorder (ASD) is a common child neurodevelopmental disorder, whose pathogenesis is not completely understood. Until now, there is no proven treatment for the core symptoms of ASD. However, some evidence indicates a crucial link between this disorder and GABAergic signals which are altered in ASD. Bumetanide is a diuretic that reduces chloride, shifts gamma-amino-butyric acid (GABA) from excitation to inhibition, and may play a significant role in the treatment of ASD.

Objective: The objective of this study is to assess the safety and efficacy of bumetanide as a treatment for ASD.

Methods: Eighty children, aged 3-12 years, with ASD diagnosed by Childhood Autism Rating Scale (CARS), ⩾ 30 were included in this double-blind, randomized, and controlled study. Group 1 received Bumetanide, Group 2 received a placebo for 6 months. Follow-up by CARS rating scale was performed before and after 1, 3, and 6 months of treatment.

Results: The use of bumetanide in group 1 improved the core symptoms of ASD in a shorter time with minimal and tolerable adverse effects. There was a statistically significant decrease in CARS and most of its fifteen items in group 1 versus group 2 after 6 months of treatment (p-value <0.001).

Conclusion: Bumetanide has an important role in the treatment of core symptoms of ASD.

Transcranial Magnetic Stimulation (TMS) is a non-invasive technique for analyzing the central and peripheral nervous system. TMS could be a powerful therapeutic technique for neurological disorders. TMS has also shown potential in treating various neurophysiological complications, such as depression, anxiety, and obsessive-compulsive disorders, without pain and analgesics. Despite advancements in diagnosis and treatment, there has been an increase in the prevalence of brain cancer globally. For surgical planning, mapping brain tumors has proven challenging, particularly those localized in expressive regions. Preoperative brain tumor mapping may lower the possibility of postoperative morbidity in surrounding areas. A navigated TMS (nTMS) uses magnetic resonance imaging (MRI) to enable precise mapping during navigated brain stimulation. The resulting magnetic impulses can be precisely applied to the target spot in the cortical region by employing nTMS. This review focuses on nTMS for preoperative planning for brain cancer. This study reviews several studies on TMS and its subtypes in treating cancer and surgical planning. nTMS gives wider and improved dimensions of preoperative planning of the motor-eloquent areas in brain tumor patients. nTMS also predicts postoperative neurological deficits, which might be helpful in counseling patients. nTMS have the potential for finding possible abnormalities in the motor cortex areas.

The gut microbiome interacts with the brain bidirectionally through the microbiome-gutbrain axis, which plays a key role in regulating various nervous system pathophysiological processes. Trimethylamine N-oxide (TMAO) is produced by choline metabolism through intestinal microorganisms, which can cross the blood-brain barrier to act on the central nervous system. Previous studies have shown that elevated plasma TMAO concentrations increase the risk of major adverse cardiovascular events, but there are few studies on TMAO in cerebrovascular disease and vascular cognitive impairment. This review summarized a decade of research on the impact of TMAO on stroke and related cognitive impairment, with particular attention to the effects on vascular cognitive disorders. We demonstrated that TMAO has a marked impact on the occurrence, development, and prognosis of stroke by regulating cholesterol metabolism, foam cell formation, platelet hyperresponsiveness and thrombosis, and promoting inflammation and oxidative stress. TMAO can also influence the cognitive impairment caused by Alzheimer's disease and Parkinson's disease via inducing abnormal aggregation of key proteins, affecting inflammation and thrombosis. However, although clinical studies have confirmed the association between the microbiome-gut-brain axis and vascular cognitive impairment (cerebral small vessel disease and post-stroke cognitive impairment), the molecular mechanism of TMAO has not been clarified, and TMAO precursors seem to play the opposite role in the process of poststroke cognitive impairment. In addition, several studies have also reported the possible neuroprotective effects of TMAO. Existing therapies for these diseases targeted to regulate intestinal flora and its metabolites have shown good efficacy. TMAO is probably a new target for early prediction and treatment of stroke and vascular cognitive impairment.

Background: Postsynaptic density (PSD) is an electron-dense structure that contains various scaffolding and signaling proteins. Shank1 is a master regulator of the synaptic scaffold located at glutamatergic synapses, and has been proposed to be involved in multiple neurological disorders.

Methods: In this study, we investigated the role of shank1 in an in vitro Parkinson's disease (PD) model mimicked by 6-OHDA treatment in neuronal SN4741 cells. The expression of related molecules was detected by western blot and immunostaining.

Results: We found that 6-OHDA significantly increased the mRNA and protein levels of shank1 in SN4741 cells, but the subcellular distribution was not altered. Knockdown of shank1 via small interfering RNA (siRNA) protected against 6-OHDA treatment, as evidenced by reduced lactate dehydrogenase (LDH) release and decreased apoptosis. The results of RT-PCR and western blot showed that knockdown of shank1 markedly inhibited the activation of endoplasmic reticulum (ER) stress associated factors after 6-OHDA exposure. In addition, the downregulation of shank1 obviously increased the expression of PRDX3, which was accompanied by the preservation of mitochondrial function. Mechanically, downregulation of PRDX3 via siRNA partially prevented the shank1 knockdowninduced protection against 6-OHDA in SN4741 cells.

Conclusion: In summary, the present study has provided the first evidence that the knockdown of shank1 protects against 6-OHDA-induced ER stress and mitochondrial dysfunction through activating the PRDX3 pathway.