CNS & neurological disorders drug targets最新文献

Parkinson's disease (PD) is the second most debilitating neurodegenerative movement disorder. It is characterized by the presence of fibrillar alpha-synuclein amassed in the neurons, known as Lewy bodies. Certain cellular and molecular events are involved, leading to the degeneration of dopaminergic neurons. However, the origin and implication of such events are still uncertain. Nevertheless, the role of microRNAs (miRNAs) as important biomarkers and therapeutic molecules is unquestionable. The most challenging task by far in PD treatment has been its late diagnosis followed by therapeutics. miRNAs are an emerging hope to meet the need of early diagnosis, thereby promising an improved movement symptom and prolonged life of the patients. The continuous efforts in discovering the role of miRNAs could be made possible by the utilisation of various animal models of PD. These models help us understand insights into the mechanism of the disease. Moreover, miRNAs have been surfaced as therapeutically important molecules with distinct delivery systems enhancing their success rate. This review aims at providing an outline of different miRNAs implicated in either PD-associated gene regulation or involved in therapeutics.

Alzheimer's disease (AD) is the most prevalent form of dementia among geriatrics. It is a progressive, degenerative neurologic disorder that causes memory and cognition loss. The accumulation of amyloid fibrils and neurofibrillary tangles in the brain of AD patients is a distinguishing feature of the disease. Therefore, most of the current therapeutic goals are targeting inhibition of beta-amyloid synthesis and aggregation as well as tau phosphorylation and aggregation. There is also a loss of the cholinergic neurons in the basal forebrain, and first-generation therapeutic agents were primarily focused on compensating for this loss of neurons. However, cholinesterase inhibitors can only alleviate cognitive symptoms of AD and cannot reduce the progression of the disease. Understanding the molecular and cellular changes associated with AD pathology has advanced significantly in recent decades. The etiology of AD is complex, with a substantial portion of sporadic AD emerging from unknown reasons and a lesser proportion of early-onset familial AD (FAD) caused by a mutation in several genes, such as the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. Hence, efforts are being made to discover novel strategies for these targets for AD therapy. A new generation of AChE and BChE inhibitors is currently being explored and evaluated in human clinical trials for AD symptomatic treatment. Other approaches for slowing the progression of AD include serotonergic modulation, H3 receptor antagonism, phosphodiesterase, COX-2, and MAO-B inhibition. The present review provides an insight into the possible therapeutic strategies and their molecular mechanisms, enlightening the perception of classical and future treatment approaches.

Introduction: Several COVID-19 vaccines have been implemented. However, some side effects of the vaccine have been reported, which are sometimes very harmful. Reported cases and data are still very limited regarding the psychiatric side effects of the COVID-19 vaccine. To our knowledge, only one case has been reported. In this paper, we report the case of a patient who presented an acute depressive episode 24 hours after receiving his first dose of the BNT162b2mRNA vaccine.

Case report: The case was a 26-year-old man with a history of Down syndrome with moderately good autonomy for daily routine tasks. The patient, who presented hypothyroidism at 10 years old and schizophrenia at 15 years old, was doing well before the vaccination and received his first dose of the BNT162b2mRNA vaccine. Twenty-four hours later, he presented depressive symptoms that resolved spontaneously after one week. Then, fifteen days later, the symptoms reappeared, and the episode lasted for 5 weeks. The patient received 10 mg/day of escitalopram besides his usual treatment. The depressive symptoms improved considerably by the second day of treatment.

Discussion: The presented case illustrated significant diagnostic challenges, especially when taking into account the sequential relationship between the COVID-19 vaccine and the occurrence of depressive symptoms. A single case of depression has been reported after the administration of the COVID-19 vaccine. Scientific evidence suggests the important role of the immune system in the pathophysiology of various psychiatric disorders, including depression.

Conclusion: Health professionals must take into consideration the potential psychiatric side effects even being rare so far, especially in vulnerable subjects. Further studies are required to establish the causal effects of depressive symptoms occurring during the weeks following the COVID-19 vaccine bolus injection.

Background: Depression is a debilitating disorder that at present lacks a reliable biomarker to aid in diagnosis and early detection. Recent advances in computational analytic approaches have opened up new avenues in developing such a biomarker by taking advantage of the wealth of information that can be extracted from a person's speech.

Objective: The current review provides an overview of the latest findings in the rapidly evolving field of computational language analysis for the detection of depression. We cover a wide range of both acoustic and content-related linguistic features, data types (i.e., spoken and written language), and data sources (i.e., lab settings, social media, and smartphone-based). We put special focus on the current methodological advances with regard to feature extraction and computational modeling techniques. Furthermore, we pay attention to potential hurdles in the implementation of automatic speech analysis.

Conclusion: Depressive speech is characterized by several anomalies, such as lower speech rate, less pitch variability and more self-referential speech. With current computational modeling techniques, such features can be used to detect depression with an accuracy of up to 91%. The performance of the models is optimized when machine learning techniques are implemented that suit the type and amount of data. Recent studies now work towards further optimization and generalizability of the computational language models to detect depression. Finally, privacy and ethical issues are of paramount importance to be addressed when automatic speech analysis techniques are further implemented in, for example, smartphones. Altogether, computational speech analysis is well underway towards becoming an effective diagnostic aid for depression.

Parkinson's disease (PD) is a chronic and progressive neurological disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The pathogenesis of PD is strongly related to mitochondrial dysfunction, oxidative stress, and neuroinflammation. This indicates that PD can be treated with anti-oxidative substitutes and anti-inflammatory compounds. The neuroprotective and anti-inflammatory effects of peroxisome proliferator-activated receptor γ (PPAR-γ) agonists decrease cell death and halt the increase in neurodegeneration, which is why they have been given a lot of importance in research. Antidiabetic and anti-inflammatory effects have been observed to be generated by pioglitazone (PG), a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist that regulates neural plasticity in various neurodegenerative disorders. The neuroprotective and anti-inflammatory effects of PG are assessed in this article. It was found that the patients with DM who received PG treatment were noticeably at a lower risk of PD. However, some clinical studies have not proven a strong link between the therapeutic effects of PG on PD. As per suggestions of preclinical studies, the therapeutic effects of PG treatment include; increased life expectancy of neurons, decreased oxidative stress, halted microglial activity, lower inflammation (reduced NF-κB, COX-2, and iNOS), reduced mitochondrial dysfunction, rise in motor function (motor agility) and non-motor function (lowered cognitive dysfunction). In conclusion, we determined that PG exerts neuroprotective and anti-inflammatory effects in PD models and it can be considered a potential therapeutic candidate for PD.

Brain disorders are currently one of the world's most serious and difficult health issues. These brain disorders are accountable for a massive number of morbidities and mortalities around the world. The current treatments of these disorders are frequently accompanied by severe side effects and cause a detrimental effect on health. Recently, plant flavonoids have sparked a surge in public and scientific attention because of their alleged health-promoting impact and almost no adverse repercussions. Also, scientific research has shown that phytochemicals possess numerous neuroprotective properties under in vivo and in vitro conditions. Chrysin is a therapeutic phytochemical that falls under the class of flavonoids based on its structure. The biological activities and pharmacological effects of chrysin include anticancer, antioxidant, and anti-inflammatory activities as well as amyloidogenic and neurotrophic effects. These therapeutic abilities of chrysin are attributed to its structural diverseness arising in ring-A and lack of oxygenation in B and C rings. Several studies have highlighted the rising significance of chrysin in a variety of brain illnesses, like Alzheimer's disease, Parkinson's disease, depression, anxiety, brain tumours, epilepsy, multiple sclerosis, traumatic brain injury, spinal cord injury, and ischemic stroke. This study depicts the relationship of chrysin with different brain-related disorders and discusses the mechanisms responsible for the potential role of chrysin as a pharmacological agent for the treatment and management of different brain disorders based on the results of several preclinical studies and taking into account the therapeutic effects of the compound.

Background and objective: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta, resulting in the loss of dopamine in the striatum, leading thus to the PD classic movement symptoms: resting tremor, rigidity, and bradykinesia/akinesia. Furthermore, Levodopa's efficacy declines with long-term use, generating serious motor complications. Neuroprotection implies the use of different agents exhibiting various neuroprotective strategies to prevent brain degeneration and neuron loss. The present review aims to summarize and analyze the natural neuroprotective compounds that have been tested against PD induced by the 6-hydroxydopamine (6-OHDA) in zebrafish.

Results: The current study collected 23 different natural substances, divided into five distinct categories, namely herbal extracts, herbal formulations, bioactive compounds, marine products, and marine extracts. They modulate various signaling pathways involved in PD pathogenesis and exhibit specific activities such as an anxiolytic profile, improving locomotor impairment, restoring memory troubles, preventing DNA loss, inhibiting acetylcholinesterase, reducing lipid peroxidation and antiinflammatory activity, and enhancing the brain antioxidant enzymes.

Conclusion and perspectives: This review discusses the most promising natural neuroprotective compounds that have been evaluated for their potential efficiency on the 6-OHDA-induced lesions in the zebrafish model. These natural substances deserve further consideration for determination of their optimum concentrations, bioavailability, and their ability to cross the blood-brain-barrier to exert their effects on PD. Furthermore, a complete understanding of the molecular mechanisms involved in PD and larger epidemiologic and randomized clinical trials in humans is also required.

Background: Epilepsy is a common neurological disorder affecting more than 70 million people worldwide. Despite numerous efforts on new antiepileptic drugs, approximately one-third of epilepsy patients suffer from uncontrolled seizures. It leads to serious psychosocial consequences, cognitive problems, and decreased quality of life.

Objective: Our previous studies have shown that N. incisum root extract (NRE) can improve cognitive dysfunction in Alzheimer's disease (AD) mice. In addition, our research shows that AD and epilepsy have pathological mechanisms overlapping. Therefore, we tried to investigate whether NRE can ameliorate the seizures of epileptic mice in this study.

Methods: NRE-treated mice group was given an oral administration with 1 g/kg/d for 7 days. On the 8th day, mice were exposed to PTZ (i.p. injection) to induce epilepsy. Then the cognitive tests of mice in the water maze were carried out, and the biochemical indexes and pathological tests were carried out after the mice were sacrificed.

Results: SOD level in the NRE group was significantly higher than that in the PTZ group, while MDA, TNF-α, and IL-1β levels were decreased. The cognitive ability of NRE-treated mice was significantly improved compared with the PTZ group. Immunohistochemistry (IHC) results showed that the activation of microglia and astrocytes in the hippocampus and cortex of NRE mice were inhibited.

Conclusion: This study suggests that NRE can alleviate epilepsy and improve cognitive function in mice with epilepsy, and its mechanism may be through reducing inflammation and enhancing antioxidant defense.

Multiple Sclerosis (MS) is a multifactorial, neurodegenerative, and inflammatory demyelination disease with incomplete remyelination in the CNS. It would be more informative to reveal the underlying molecular mechanisms of MS. Molecular mechanisms involving epigenetic changes play a pivotal role in this disease. Epigenetic changes impact gene expression without altering the underlying DNA sequence. The main epigenetic modifications that play a key role in the regulation of gene expression principally include DNA methylation, histone modifications, and microRNA- associated post-transcriptional gene silencing. In this review, we summarize the dynamics of epigenetic changes and their relation to environmental risk factors in MS pathogenesis. Studies suggest that epigenetic changes have a role in the development of MS and environmental risk factors, such as vitamin D, smoking, and Epstein-Barr virus infection seem to influence the development and susceptibility to MS. Investigating epigenetic and environmental factors can provide new opportunities for the molecular basis of the diseases, which shows complicated pathogenesis. Epigenetic research has the potential to complete our understanding of MS initiation and progression. Increased understanding of MS molecular pathways leads to new insights into potential MS therapies. However, there is a need for in vivo evaluation of the role of epigenetic factors in MS therapy. It would be more valuable to indicate the role of various epigenetic factors in MS.

It is well established that learning and memory are complex processes. They involve and recruit different brain modulatory neurotransmitter systems. Considerable evidence points to the involvement of dopamine (DA) in learning and memory. Manifestations of the synaptic spatial localization of the effect of DA have gained a great deal of interest. Despite the molecular cloning of the five DA receptor subtypes, the underlying signaling of the DA receptors in spatial learning and memory is less compelling. Fluctuations in the DA level in the brain are associated with many diseases that comprise deficits in learning and memory, including Parkinson's disease, Huntington's disease, schizophrenia, and Alzheimer's disease. This review aims to briefly summarize existing information regarding the memory performance modified by DA. The signaling of the DA system, particularly examining the origin of DA-modulated memory, is also discussed. Then, several kinds of memories in which DA plays a critical role, including reward signaling, working memory, and long-term plasticity, as well as memory consolidation, are also described. Finally, memory impairment in some DA-related neurological disorders is also examined.