CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 22, Issue 1, 2023

G-protein-coupled receptors (GPCRs) are activated by manifold neurotransmitters, and their activation, in turn, evokes slow synaptic transmission. They are profoundly related to numerous psychiatric and neurological disorders such as schizophrenia and Parkinson's disease. The significant malady indications for GPCR modulators demonstrate a change towards obesity, diabetes, and Alzheimer's disease, while other central nervous system disorders persist highly represented. GPR52, GPR6, and GPR8 are recognised as orphan GPCRs, co-exist either with both the dopamine D2 and D1 receptors in neurons of the basal ganglia or with the dopamine D2 receptor alone, and recommend that between these orphan receptors, GPR52 has the maximum potential of being a therapeutic psychiatric receptor. Genetically modified creature models and molecular biological investigations have suggested that these improved GPCRs could be potential therapeutic psychiatric receptors. In this perspective, the role of molecular targets in GPCR-mediated signalling has been discussed that would be novel drug design and discovery options for a scientist to elaborate previous knowledge with modern techniques.

For the development and maintenance of neuron networks in the brain, epigenetic mechanisms are necessary, as indicated by recent findings. This includes some of the high-order brain processes, such as behavior and cognitive functions. Epigenetic mechanisms could influence the pathophysiology or etiology of some neuronal diseases, altering disease susceptibility and therapy responses. Recent studies support epigenetic dysfunctions in neurodegenerative and psychiatric conditions, such as Alzheimer's disease (AD). These dysfunctions in epigenetic mechanisms also play crucial roles in the transgenerational effects of the environment on the brain and subsequently in the inheritance of pathologies. The possible role of gonadal steroids in the etiology and progression of neurodegenerative diseases, including Alzheimer’s disease, has become the subject of a growing body of research over the last 20 years. Recent scientific findings suggest that epigenetic changes, driven by estrogen and androgens, play a vital role in brain functioning. Therefore, exploring the role of estrogen and androgen-based epigenetic changes in the brain is critical for the deeper understanding of AD. This review highlights the epigenetic modifications caused by these two gonadal steroids and the possible therapeutic strategies for AD.

The blood-brain barrier (BBB) is considered an important protective barrier in the central nervous system (CNS). The barrier is mainly formed by endothelial cells (ECs) interconnected by various junctions such as tight junctions (TJs), gap junctions, and adherent junctions. They collectively constitute an intensive barrier to the transit of different substances into the brain, selectively permitting small molecules to pass through by passive movement but holding off large ones such as peptides and proteins to cross the brain. Hence some molecules selectively transfer across the BBB by active routes via transcytosis. The BBB also forms a barrier against neurotoxins as well as pathogenic agents. Although various CNS disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) could hamper the integrity of the border. Nevertheless, the BBB acts as a barrier for CNS disorders treatment because it prevents the drugs from reaching their target in the CNS. In recent years, different strategies, including osmotic disruption of BBB or chemical modification of drugs, have been used to transfer the chemotherapeutic agents into brain substances. Nowadays, nanoparticles (NPs) have been used as an effective and non-invasive tool for drug delivery and diagnosis of CNS disorders. In this review, we discuss the structural characteristic of BBB, safe passageways to cross the BBB, and the relation of barrier lesions with different CNS disorders. In the end, we explore the progress in drug delivery, diagnosis, imaging, and treatment of CNS disorders using nanoparticles.

Although the prevalence of brain injury and related neurodevelopmental disabilities resulting from preterm birth are major public health concerns, there are no definite neuroprotective strategies to prevent or reduce brain injury. The pattern of brain injury seen in preterm infants has evolved into more subtle lesions that are still essential to diagnose regarding neurodevelopmental outcomes. There is no specific effective method for the treatment of premature infant brain injury, and the focus of clinical treatment is still on prevention. Prevention of this injury requires insight into the pathogenesis, but many gaps exist in our understanding of how neonatal treatment procedures and medications impact cerebral hemodynamics and preterm brain injury. Many studies provide evidence about the prevention of premature infant brain injury, which is related to some drugs (such as erythropoietin, melatonin, mesenchymal stem cells, etc.). However, there are still some controversies about the quality of research and the effectiveness of therapy. This review aims to recapitulate the results of preclinical studies and provide an update on the latest developments around etiological pathways, prevention, and treatment.

Background: Major depression is a debilitating, sometimes fatal disorder, deteriorating the quality of life and well-being. Escitalopram showed highly selective and dose-dependent inhibitory activity on human serotonin transport. Selective serotonin reuptake inhibitors (SSRIs) are the first-line drugs to manage major depressive disorder (MDD). Objective: The objective of this study is to explore the therapeutic potential of escitalopram, a clinically approved drug to manage MDD and panic disorders. Methods: It emphasizes comparative and clinical trial studies with several pharmacological targets reviewed from the data available on PubMed, Science Direct, Clinicaltrails.gov, and from many reputed foundations. Results: To highlight the clinical efficacy, safety, recent development, and stable formulation of escitalopram with an increased bioavailability profile. Evidence-based on the available clinical and pharmacoeconomic data, escitalopram represents an effective first-line treatment option for MDD patients. Conclusion: The present review highlights the placebo-controlled clinical studies and the recent development that can be helpful for further research perspectives.

Neuropsychiatric disorders that affect the central nervous system cause considerable pressures on the health care system and have a substantial economic burden on modern societies. The present treatments based on available drugs are mostly ineffective and often costly. The molecular process of neuropsychiatric disorders is closely connected to modifying the genetic structures inherited or caused by damage, toxic chemicals, and some current diseases. Gene therapy is presently an experimental concept for neurological disorders. Clinical applications endeavor to alleviate the symptoms, reduce disease progression, and repair defective genes. Implementing gene therapy in inherited and acquired neurological illnesses entails the integration of several scientific disciplines, including virology, neurology, neurosurgery, molecular genetics, and immunology. Genetic manipulation has the power to minimize or cure illness by inducing genetic alterations at endogenous loci. Gene therapy that involves treating the disease by deleting, silencing, or editing defective genes and delivering genetic material to produce therapeutic molecules has excellent potential as a novel approach for treating neuropsychiatric disorders. With the recent advances in gene selection and vector design quality in targeted treatments, gene therapy could be an effective approach. This review article will investigate and report the newest and the most critical molecules and factors in neuropsychiatric disorder gene therapy. Different genome editing techniques available will be evaluated, and the review will highlight preclinical research of genome editing for neuropsychiatric disorders while also evaluating current limitations and potential strategies to overcome genome editing advancements.

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic neurons and intraneuronal accumulation of protein aggregates. The exact mechanisms leading to neuronal death in PD are not fully understood, but several different molecular pathways are involved, leading to the concept that molecular subtypes may coexist in the nosological spectrum of PD. To this respect, immune system activation, both in the periphery and inside the central nervous system, was detected as a common trait of several pathogenic pathways of PD. The current working hypothesis implies that immune cells shift towards a proinflammatory phenotype and trigger the production of neurotoxic cytokines, ultimately contributing to neurodegeneration. While it is very important to understand how commonly used antiparkinson drugs interact with such changes, the search for treatments that may directly or indirectly modulate immune function is a great opportunity for disease modification.

Pregnancy is a sensitive period when women experience major hormonal and psychological changes. A high prevalence of the symptoms of depression and manifested major depression rates have been reported during this period, leading to negative outcomes both for mothers and the offspring. Despite its prevalence, the aetiology of depression is not yet fully understood. Nonetheless, alterations in cortisol levels have been proposed as a reliable biomarker to identify pregnant women at risk of perinatal depression. Hair cortisol has recently been extensively used in bio-psychological studies as a suitable non-invasive biomarker for several neuropsychiatric disorders. Various studies have published evidence regarding the relationship between cortisol fluctuations during the perinatal period, measured both in hair and in other substrates, and the onset of perinatal symptoms of depression. This current review provides an overview of cortisol level changes measured in women’s hair during pregnancy or the postpartum period and its association with perinatal symptoms of depression. Further studies, including repetitive measurement of both hair cortisol and depression throughout the prenatal period, must be performed to clarify the relationship between cortisol levels and perinatal symptoms of depression.

Due to rising environmental and global public health concerns associated with environmental contamination, human populations are continually being exposed to environmental toxicants, including physical chemical mutagens widespread in our environment causing adverse consequences and inducing a variety of neurological disorders in humans. Physical mutagens comprise ionizing and non-ionizing radiation, such as UV rays, IR rays, X-rays, which produces a broad spectrum of neuronal destruction, including neuroinflammation, genetic instability, enhanced oxidative stress driving mitochondrial damage in the human neuronal antecedent cells, cognitive impairment due to alterations in neuronal function, especially in synaptic plasticity, neurogenesis repression, modifications in mature neuronal networks drives to enhanced neurodegenerative risk. Chemical Mutagens including alkylating agents (EMS, NM, MMS, and NTG), Hydroxylamine, nitrous acid, sodium azide, halouracils are the major toxic mutagen in our environment and have been associated with neurological disorders. These chemical mutagens create dimers of pyrimidine that cause DNA damage that leads to ROS generation producing mutations, chromosomal abnormalities, genotoxicity which leads to increased neurodegenerative risk. The toxicity of four heavy metal including Cd, As, Pb, Hg is mostly responsible for complicated neurological disorders in humans. Cadmium exposure can enhance the permeability of the BBB and penetrate the brain, driving brain intracellular accumulation, cellular dysfunction, and cerebral edema. Arsenic exerts its toxic effect by induction of ROS production in neuronal cells. In this review, we summarize the molecular mechanism and mechanistic effects of mutagens in the environment and their role in multiple neurological disorders.

Background: Human’s existence has become more stressful these days, most likely for the sake of improving one's lifestyle and fulfilling one's aspirations and needs. Depression is the most frequent neurological disorder, which affects millions of individuals worldwide. In clinical research, depression is the second most frequent chronic disease. A variety of herbal medications thought to have antidepressant-like effects have been reported in ancient pharmacopoeias from around the world. These provide several prospective chemicals that could be developed into modern mental medications while also causing no noticeable negative effects. Objective: The review is written to provide herbal treatment and comprehensive information about depression. Methods: Plants and plant formulations that were found effective in the treatment of depression are thoroughly reviewed. The antidepressant efficacies of medicinal plants, as well as their dosages, are investigated using experimental models. The review article contains 140 plants possessing antidepressant properties, 11 commercial formulations, and 25 active/isolated ingredients, as well as their chemical structure, which have been thoroughly reviewed with antidepressant activity after studying 283 references. Results: Literature revealed that a variety of medicinal plants are effective for the treatment of depression such as Hypericum perforatum, Catha edulis, Tinospora cordifolia, Curcuma longa, Ferula foetida, Rhodio larosea, Glycyrrhiza glabra, Crocus sativus, Ocimumba silicum and Embelica officinalis. Conclusion: Potential compounds isolated from medicinal plants for the treatment of depressive disorders need to be established and herbal plant research could aid in this endeavour.

Background: A substantial amount of evidence indicates that long-term arsenic exposure leads to various types of pathological complications, especially cognitive dysfunction. Objective: The present study was designed to assess the neuroprotective potential of edaravone (a potent free radical scavenger) against arsenic-induced neurotoxicity in Wistar rats. Methods: Adult male Wistar rats were randomly divided into five groups. Arsenic (20 mg/kg/day; p.o.) and Edaravone (5 and 10 mg/kg/day; i.p.) were administered in different experimental groups for 28 days. Results: The results of various behavioral test paradigms revealed that arsenic caused significant learning and memory deficits, along with anxiety-like behavior. In biochemical analysis, we found marked elevations of oxidative-nitrosative stress (indicated by augmentation of lipid peroxidation and nitrite) and a reduction of glutathione levels in the hippocampus and frontal cortex region of arsenictreated rats. Moreover, arsenic administration caused mitochondrial complexes impairment and reduction of acetylcholinesterase level. On the other hand, chronic treatment with edaravone (10 mg/kg) significantly ameliorated the arsenic-induced behavioral deficits and neurochemical anomalies. Conclusion: This study suggests that edaravone confers neuroprotection against arsenic-induced memory impairment and anxiety-like behavior, which may be attributed to the inhibition of oxidativenitrosative stress and amelioration of cholinergic and mitochondrial functions.

Background: Recent studies have uncovered that vitexin compound B-1 (VB-1) can protect neurons against hypoxia/reoxygenation (H/R)-induced oxidative injury through suppressing NOX4 expression. Objective: The aims of this study are to investigate whether VB-1 can protect the rat brain against ischemia/ reperfusion (I/R) injury and whether its effect on NOX4 expression is related to modulation of certain miRNAs expression. Methods: Rats were subjected to 2 h of cerebral ischemia followed by 24 h of reperfusion to establish an I/R injury model, which showed an increase in neurological deficit score and infarct volume concomitant with an upregulation of NOX4 expression, increase in NOX activity, and downregulation of miR-92b. Results: Administration of VB-1 reduced I/R cerebral injury accompanied by a reverse in NOX4 and miR-92b expression. Similar results were achieved in a neuron H/R injury model. Next, we evaluated the association of miR-92b with NOX4 by its mimics in the H/R model. H/R treatment increased neurons apoptosis concomitant with an upregulation of NOX4 and NOX activity while downregulation of miR-92b. All these effects were reversed in the presence of miR-92b mimics, confirming the function of miR-92b in suppressing NOX4 expression. Conclusion: We conclude the protective effect of VB-1 against rat cerebral I/R injury through a mechanism involving modulation of miR-92b/NOX4 pathway.