CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 22, Issue 6, 2023

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.

Parkinson's Disease (PD), known as Parkinsonism, is a neurodegenerative disease that mainly affects the elderly and is characterized by an extensive and progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Owing to genetic, environmental, and lifestyle changes, the incidence of PD has recently risen among adults. The most widely used PD treatment strategies include the use of dopamine agonists, anticholinergics, and enzyme inhibitors. The aquatic flora and fauna have become the emerging source of novel, structurally diverse bioactive compounds and, at present, the researchers concentrate their efforts on isolating, characterizing, and identifying many secondary metabolites of different nature to treat various disorders, including, neuroprotective marine natural products (MNPs). The bioactive peptides, tannins, carotenoids, alkaloids, polyunsaturated fatty acids (PUFA), and sulfated polysaccharides from the MNP’s and their synthetic derivatives have demonstrated important neuroprotective activity in preclinical studies through multiple mechanisms. An extensive literature survey was carried out, and published articles from PubMed, Scifinder, Google Scholar, Web of Science, and Scopus were carefully reviewed to compile information on the MNPs to treat PD. This current review focus on neuroprotective MNPs and their probable biological pathways to treat PD based on their structure and bioactivities reported from 1990 to 2020.

Background: Chemotherapy with the oral alkylating agent temozolomide still prevails as a linchpin in the therapeutic regimen of glioblastoma alongside radiotherapy. Because of the impoverished prognosis and sparse chemotherapeutic medicaments associated with glioblastoma, the burgeoning resistance to temozolomide has made the whole condition almost irremediable. Objective: The present review highlights the possible mechanisms of drug resistance following chemotherapy with temozolomide. Methods: The review summarizes the recent developments, as published in articles from Scopus, PubMed, and Web of Science search engines. Description: One of the prime resistance mediators, O-6-methylguanine-DNA methyltransferase, upon activation, removes temozolomide-induced methyl adducts bound to DNA and reinstates genomic integrity. In the bargain, neoteric advances in the conception of temozolomide resistance have opened the door to explore several potential mediators like indirect DNA repair systems, efflux mechanisms, epigenetic modulation, microenvironmental influences, and autophagy-apoptosis processes that constantly lead to the failure of chemotherapy. Conclusion: This review sheds light on recent discoveries, proposed theories, and clinical developments in the field of temozolomide resistance to summarize the complex and intriguing involvement of oncobiological pathways.

Stroke is the leading cause of morbidity and mortality in diabetic patients. Diabetes alters the endothelial function and disrupts brain pathways, resulting in a variety of systemic metabolic complications. Diabetics not only have impaired neurotransmission, but also have progressive neurodegeneration, which leads to long-term neurological complications. Diabetes risk factors and physiology alter the frequency and severity of cardiovascular and cerebrovascular events, necessitating more hospitalizations. Stroke and diabetes have a mutually reinforcing relationship that worsens their outcomes. Diabetes has far-reaching systemic consequences for human physiology as a metabolic syndrome. As a result, diabetic stroke patients require dual-therapeutics with dual protection. Scientific researchers have made tremendous progress in diabetes-related stroke and its therapeutics over the last few decades. We have summarised diabetic brain and associated risk factors, co-morbidities, biomarkers, and hyperglycemia-associated neurovascular insult and cognitive demur. In addition to providing an overview of the effects of hyperglycaemia on brain physiology, this article aims to summarise the evidence from current glucose-lowering treatment, recent advances in stroke therapeutics as well as exploring stem cell therapy in the management of diabetes-associated stroke.

Stroke is a physiological disorder involving a prolonged local interruption of cerebral blood flow. It leads to massive neuronal death and causes short-term or long-lasting functional impairment. Most stroke victims regain some neural function weeks or months following a stroke, but this recovery can plateau six months or more after the injury. The goal of stroke therapy is the rehabilitation of functional capabilities, especially those affecting the patient’s autonomy and quality of life. Recent clinical and animal studies combining acute dextro-amphetamine (d-AMPH) administration with rehabilitative training (RT) have revealed that this treatment has significant remedial effects. The review aims to examine the synergistic therapeutic effects of d-amphetamine coupled with RT, administered during the early or late subacute period, on neuronal activation, anatomic plasticity, and skilled motor function in a middle-aged rodent stroke model. The treatment will also include magnetic field stimulation. This review will help increase understanding of the mechanism of d-amphetamine coupled with RT and magnetic field stimulation and their converging therapeutic effects for stroke recovery.

Coronavirus disease 2019 (COVID-19) is a primary respiratory disease with an alarming impact worldwide. COVID-19 is caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and presents various neurological symptoms, including seizures. SARS-CoV-2 shows neuroinvasive and neurotropic capabilities through a neuronal angiotensin-converting enzyme 2 (ACE2), which is also highly expressed in both neuronal and glial cells. Therefore, SARS-CoV-2 can trigger neuroinflammation and neuronal hyperexcitability, increasing the risk of seizures. Olfactory neurons could be an exceptional neuronal pathway for the neuroinvasion of respiratory viruses to access the central nervous system (CNS) from the nasal cavity, leading to neuronal injury and neuroinflammation. Although neuronal ACE2 has been widely studied, other receptors for SARS-CoV-2 in the brain have been proposed to mediate viral-neuronal interactions with subsequent neurological squeals. Thus, the objective of the present critical review was to find the association and mechanistic insight between COVID-19 and the risk of seizures.

Aim: The main aim of present study to assess depression and various neurotransmitters involved in it with their evaluating models. Background: Depression is a common ailment that can be recurrent or even become chronic. According to the National Service Framework for Mental Health (released in 1999 by the Department of Health), people with depression should continue to be treated primarily in primary care settings. Despite mounting evidence that general practitioners could do a better job of detecting and treating depression, little research has been done on the perspectives of general practitioners who treat patients who are depressed. Depression (major depressive disorder) is a widespread and significant medical condition that has a negative impact on feeling, thinking, and behaviour. Objectives: The primary goal of this study was to gather data on depression, as well as to discuss several methods for evaluating antidepressant drug response based on physical activities and neurotransmitters. Methods: Antidepressant activity of various medications can be tested using two different types of studies, including in vivo and in vitro, according to the review. Results: Depression is characterized by a persistent sense of sadness, insomnia, lack of concentration, slowness in activity, restlessness, social isolation and a loss of interest that prevents you from doing normal things. There are several types of depression, with symptoms ranging from mild to severe. Depression is caused by a combination of factors and conditions, rather than a single factor. Major depression is a mental condition marked by feelings of inadequacy, hopelessness, decreased activity, sadness and mood swings, which seriously disrupt and negatively affect a person's life, sometimes, leading to suicidal thoughts. The quest for a better understanding of the causes of depression and the development of more effective treatments is critical. According to clinical and preclinical research, stress appears to be a crucial mediator in the pathophysiology of depression. Using experimental models, depression may be assessed based on several physical parameters such as locomotor activity, rearing, defecation, and the number of centre square entries (in vivo and in vitro). Biological parameters may also be used to locate it. Conclusion: Unhappiness and loss of interest in previously enjoyed activities are the symptoms of depression. It can cause emotional and physical problems, as well as a decrease in the ability to function together at work and at home. Finally it has been concluded that various neurotransmitters are involved in depression at the synaptic cleft which can be controlled using various synthetic and herbal drugs through in vitro and in vivo evaluating models.

Background: COVID-19 (coronavirus disease of 2019) occurs due to the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It uses angiotensin-converting enzyme- 2 (ACE-2) as its primary receptor to enter the host cell. Recent reports suggest that this pathogen also has a large impact on the CNS alongside other organs. Various inflammatory mediators, such as cytokines, chemokines, and numerous metabolites, are poorly regulated during infection as well as in several psychiatric diseases, which leads to conditions of hypoxia and cytokine storm. The persistence of COVID-19 infection may also result in aggravation of the already present neuro-psychiatric symptoms in patients. Methods: We systematically searched various sources of journals and assessed the varied neurological routes of propagation and pathogenesis of SARS-CoV-2 neurotoxicity, like ACE2-mediated neuroinvasion induced hypoxia and the cytokine storm syndrome. Several case studies were also referred to obtain a better idea of the current mental health scenario as a consequence of infection and inflammation due to SARS-CoV-2. Conclusion: Several risk factors for the causation of mental health issues during as well as after the infection include female gender, presence of necrosis, and pain in avascular regions. Most psychiatric disorders are directly associated with the socioeconomic and psychosocial changes that have occurred as a consequence of the pandemic. These psychiatric manifestations have only started to unravel, which calls for the development of faster means of diagnosis and integrated pharmacological and epidemiological studies to curb the growing rate of neuronal complications as well as mortality.

Introduction: The efficacy of oxytocin in the treatment of autism spectrum disorder (ASD) has not been fully characterized. This systematic review and meta-analysis study evaluated randomized controlled trials (RCTs) on the treatment of intranasally administered oxytocin for autism. Methods: The study was conducted in accordance with the PRISMA statement. Two authors searched Scopus, PubMed/ Medline, Google Scholar, and Web of Science search engines and databases from inception through December 2020. Quality assessment was carried out by with the “ROB-2, Cochrane collaboration's tool”. The random-effects model was used for pooled analyses. I2 and Q tests were used to investigate study heterogeneity. The visual inspection of funnel plots along with Egger’s regression asymmetry test was used to assess the potential sources of publication bias. Results: Ten RCTs were selected for the systematic review. No study corroborated the efficacy of oxytocin for the treatment of anxiety and repetitive behavior. One out of 4 studies reported clinical improvement in severity, and 1 out of 6 studies indicated improvement in social function. Our metaanalyses findings suggest that oxytocin shows no significant efficacy in the treatment of anxiety (SMD: -0.168, SE= 0.112; 95% CI: -0.387, 0.050, p = 0.132), repetitive behavior (SMD: -0.078, SE= 0.155; 95% CI: -0.382, 0.225, p = 0.614), social function (SMD: -0.018, SE= 0.133; 95% CI: -0.279, 0.242, p = 0.891) and severity (SMD: -0.084, SE= 132; 95% CI: -0.343, 0.175, p = 0.524) of autism. No significant heterogeneity nor publication bias were observed between studies. Conclusion: Our findings failed to corroborate the efficacy of oxytocin in the treatment of ASD. Nonetheless, given the several limitations of our study, the results should be interpreted cautiously and stimulate future research on this timely topic.

Background: Many studies in vitro compared the onset of action, maximum efficacy, and duration of botulinum toxin type A (BoNT/A) preparations. Objective: In this study, we analyzed the onset of action of BoNT/A preparation free of complexing proteins in patients with upper limb spasticity post stroke up to 30 days after treatment. Methods: 75 patients affected by Biceps Brachii spasticity were enrolled. Outcome measures were instrumental muscle tone modification (myometric measurement), improvement of Modified Ashworth Scale (MAS), improvement of elbow’s passive extension, and improvement of compound muscle action potential (cMAP) evaluated by electroneurography. We analyzed data at t0 (pre-injection), t1 (1 day after), t2 (7 days after), t3 (14 days after), and t4 (30 days after). Results: All measurements decreased at t2, t3, and t4 with initial improvement at t2 and maximum improvement at t4; no statistical difference at t1 was found. Conclusion: This study demonstrated the onset of Incobotulinumtoxin A efficacy started after 7 days; this rapid action and efficacy of BoNT/A preparation could improve an intensive rehabilitation program after some days post-injection. Early clinical onset of action could be by the absence of complexing proteins in the preparation.

Background: Neuropathic pain has become a contributor to the global burden of illness. However, the currently available drugs exhibit inadequate pain relief and significant side effects. Our previous study demonstrated that the essential oil of Ageratum conyzoides exerts potent antineuropathic pain activity through opioid receptor activation. Precocene II, longifolene, and caryophyllene are the largest component of the A. conyzoides essential oil. Objective: The objective of the study was to determine the anti-neuropathic pain activity of precocene II, longifolene, and caryophyllene as single agents and in combination with pregabalin. Possible mechanisms of action involving the opioid receptor, ATP-sensitive potassium channel, and gammaaminobutyric acid (GABA) were further investigated. Methods: The experimental animals (male mice Swiss Webster) were divided randomly into seven groups, namely, Normal control (naïve mice), Negative control (CMC 1%), Sham (CMC 1%), Positive control (Pregabalin 0,195 mg/ 20 g BW of mice), Test I (Precocene II 21.09 mg/Kg BW), Test II (Longifolene 9.94 mg/Kg BW), and Test III (Caryophyllene 3.64 mg/Kg BW). Each group contained 3 animals. The test groups that demonstrated anti-neuropathic pain activity were further tested in combination with pregabalin, followed by mechanistic studies. The negative, positive, and test I-III groups were induced with chronic constriction injury. Results: The results of the study demonstrated that caryophyllene and longifolene, but not precocene II, exerted anti-neuropathic pain activity. The caryophyllene was shown to involve in the activation of opioid receptors and ATP-sensitive potassium channels. It was also reported to increase GABA concentration in the spinal cord. We further found that longifolene exerted its action via opioid receptor activation. The combination of A. conyzoides essential oil, longifolene, or caryophyllene with pregabalin demonstrated additive anti-neuropathic pain activity. Conclusion: Taken together, the results of the present study suggested that the A. conyzoides essential oil and caryophyllene have the potential to be developed as novel drugs to treat neuropathic pain.

Background: Malaria is considered one of the life-threatening mosquito-borne infectious diseases responsible for approximately more than 4,00,000 deaths every year all over the world. Plasmodium falciparum and Plasmodium vivax are widespread species, but infections caused by the former are of great concern. Objective: Among the various forms of infections associated with Plasmodium falciparum, cerebral malaria (CM) is the most severe neurological complication, accounting for almost 13% of all malariarelated mortality. The development of effective therapeutics is urgently needed to overcome the fatality of this dreadful disease. Methods: The present work attempted to design and virtually screen a chemical library of 75 molecules (N-Mannich base derivatives of primaquine bearing isatin moiety as heterocyclic) by molecular docking studies against anti-malarial target proteins-Cystein Protease Falcipain-2; Dipeptidyl Aminopeptidase- 1; Dipeptidyl Aminopeptidase-3 and Glycogen synthase Kinase-3β receptors, for evaluating their anti-malarial potential. Among all studied anti-malarial target receptors, the designed molecules showed an overall higher affinity for Dipeptidyl Aminopeptidase-3. Furthermore, the molecules were analyzed for binding affinity and drug-like properties using Lipinski rules, and 30 best hits were shortlisted and analyzed for the pharmacokinetic profile. Results: Two of these hits were found to be more toxic than primaquine, hence were omitted in further analysis. Later, these 28 hits were docked against two target proteins, (a) Plasmodium falciparum erythrocyte membrane protein-1 and (b) Intracellular adhesion molecule-1, to determine their efficiency against cerebral malaria, and the results were recorded. Analysis of docking results led to the identification of the 8 studied molecules as lead molecules which were selected for chemical synthesis, in vivo studies, and further preclinical evaluation. Conclusion: The molecule DSR 11 was predicted as the most appropriate lead molecule for anti-CM activity in the present investigation apart from the other seven molecules (DSR4, DSR26, DSR38, DSR40, DSR49, DSR56, and DSR70).