Current Neuropharmacology - Volume 20, Issue 6, 2022

Background: The piriform cortex, known as area tempestas, has a high propensity to trigger limbic epileptic seizures. Recent studies on human patients indicate that a resection containing the piriform cortex produces a marked improvement in patients suffering from intractable limbic seizures. This calls for looking back at the pharmacological and anatomical data on area tempestas. Within the piriform cortex, status epilepticus can be induced by impairing the desensitization of AMPA receptors. The mechanistic target of rapamycin complex1 (mTORC1) is a promising candidate. Objective: The present perspective aims to link the novel role of the piriform cortex with recent evidence on the modulation of AMPA receptors under the influence of mTORC1. This is based on recent evidence and preliminary data, leading to the formulation of interaction between mTORC1 and AMPA receptors to mitigate the onset of long-lasting, self-sustaining, neurotoxic status epilepticus. Methods: The perspective grounds its method on recent literature along with the actual experimental procedure to elicit status epilepticus from the piriform cortex and the method to administer the mTORC1 inhibitor rapamycin to mitigate seizure expression and brain damage. Results: The available and present perspectives converge to show that rapamycin may disrupt the seizure circuitry initiated in the piriform cortex to mitigate seizure duration, severity, and brain damage. Conclusion: The perspective provides a novel scenario to understand refractory epilepsy and selfsustaining status epilepticus. It is expected to provide a beneficial outcome in patients suffering from temporal lobe epilepsy.

Chronic pain is a common distressing neurological disorder and about 30% of the global population suffers from it. In addition to being highly prevalent, chronic pain causes a heavy economic and social burden. Although substantial progress has been achieved to dissect the underlying mechanism of chronic pain in the past few decades, the incidence and treatment of this neurological illness is yet not properly managed in clinical practice. While nerve injury-, chemotherapy- or inflammation-induced functional regulation of gene expression in the dorsal root ganglion and spinal cord are extensively reported to be involved in the pathogenic process of chronic pain, the specific mechanism of these altered transcriptional profile still remains unclear. Recent studies have shown that epigenetic mechanisms, including DNA/RNA methylation, histone modification and circular RNAs regulation, are involved in the occurrence and development of chronic pain. In this review, we provide a description of research on the role of epigenetic mechanism in chronic pain, summarize the latest clinical and preclinical advance in this field, and propose the potential directions for further research to elucidate the molecular mechanism underlying the pathogenesis of chronic pain.

Circadian rhythm sleep-wake disorders (CRSWDs) are a distinct class of sleep disorders caused by alterations to the circadian time-keeping system, its entrainment mechanisms, or a mismatch between the endogenous circadian rhythm and the external environment. The main clinical manifestations are insomnia and excessive daytime sleepiness that often lead to clinically meaningful distress or cause mental, physical, social, occupational, educational, or other functional impairment. CRSWDs are easily mistaken for insomnia or early waking up, resulting in inappropriate treatment. CRSWDs can be roughly divided into two categories, namely, intrinsic CRSWDs, in which sleep disturbances are caused by alterations to the endogenous circadian rhythm system due to chronic changes in the regulation or capture mechanism of the biological clock, and extrinsic circadian rhythm sleep-wake disorders, in which sleep disorders, such as jet lag or shift-work disorder, result from environmental changes that cause a mismatch between sleep-wakefulness times and internal circadian rhythms. Sleep diaries, actigraphy, and determination of day and night phase markers (dim light melatonin onset and core body temperature minimum) have all become routine diagnostic methods for CRSWDs. Common treatments for CRSWD currently include sleep health education, time therapy, light therapy, melatonin, and hypnotic drug therapy. Here, we review the progress in the epidemiology, etiology, diagnostic evaluation, diagnostic criteria, and treatment of intrinsic CRSWD, with emphasis on the latter, in the hope of bolstering the clinical diagnosis and treatment of CRSWDs.

G protein-coupled receptors (GPCRs) constitute the largest group of membrane receptor proteins controlling brain activity. Accordingly, GPCRs are the main target of commercial drugs for most neurological and neuropsychiatric disorders. One of the mechanisms by which GPCRs regulate neuronal function is by homo- and heteromerization, with the establishment of direct protein-protein interactions between the same and different GPCRs. The occurrence of GPCR homo- and heteromers in artificial systems is generally well accepted, but more specific methods are necessary to address GPCR oligomerization in the brain. Here, we revise some of the techniques that have mostly contributed to reveal GPCR oligomers in native tissue, which include immunogold electron microscopy, proximity ligation assay (PLA), resonance energy transfer (RET) between fluorescent ligands and the Amplified Luminescent Proximity Homogeneous Assay (ALPHA). Of note, we use the archetypical GPCR oligomer, the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer as an example to illustrate the implementation of these techniques, which can allow visualizing GPCR oligomers in the human brain under normal and pathological conditions. Indeed, GPCR oligomerization may be involved in the pathophysiology of neurological and neuropsychiatric disorders.

Backgorund: Oxidative stress is one of the main contributing factors involved in cerebral biochemical impairment. The higher susceptibility of the central nervous system to reactive oxygen species mediated damage could be attributed to several factors. For example, neurons use a greater quantity of oxygen, many parts of the brain have higher concentraton of iron, and neuronal mitochondria produce huge content of hydrogen peroxide. In addition, neuronal membranes have polyunsaturated fatty acids, which are predominantly vulnerable to oxidative stress (OS). OS is the imbalance between reactive oxygen species generation and cellular antioxidant potential. This may lead to various pathological conditions and diseases, especially neurodegenerative diseases such as, Parkinson’s, Alzheimer’s, and Huntington’s diseases. Objectives: In this study, we explored the involvement of OS in neurodegenerative diseases. Methods: We used different search terms like “oxidative stress and neurological disorders” “free radicals and neurodegenerative disorders” “oxidative stress, free radicals, and neurological disorders” and “association of oxidative stress with the name of disorders taken from the list of neurological disorders. We tried to summarize the source, biological effects, and physiologic functions of ROS. Results: Finally, it was noted that more than 190 neurological disorders are associated with oxidative stress. Conclusion: More elaborated studies in the future will certainly help in understanding the exact mechanism involved in neurological diseases and provide insight into revelation of therapeutic targets.

Depression is a prevalent disease worldwide, limiting psychosocial functioning and thequality of life. Linalool is the main constituent of some essential oils from aromatic plants, representing about 70% of these volatile concentrates. Evidence of the linalool activity on the central nervous system, mainly acting as an antidepressant agent, is increasingly abundant. This review aimed to extend the knowledge of linalool's antidepressant action mechanisms, which is fundamental for future research, intending to highlight this natural compound as a new antidepressant phytomedication. A critical analysis is proposed here with probable hypotheses of the synergic mechanisms that support the evidence of antidepressant effects of the linalool. The literature search has been conducted in databases for published scientific articles before December 2020, using relevant keywords. Several pieces of evidence point to the anticonvulsant, sedative, and anxiolytic actions. In addition to these activities, other studies have revealed that linalool acts on the monoaminergic and neuroendocrine systems, inflammatory process, oxidative stress, and neurotrophic factors, such as BDNF, resulting in considerable advances in the knowledge of the etiology of depression. In this context, linalool emerges as a promising bioactive compound in the therapeutic arsenal, capable of interacting with numerous pathophysiological factors and acting on several targets. This review claims to contribute to future studies, highlighting the gaps in the linalool knowledge, such as its kinetics, doses, routes of administration, and multiple targets of interaction, to clarify its antidepressant activity.

Background: Alzheimer's disease (AD) is a neurodegenerative impairment mainly recognized by memory loss and cognitive deficits. However, the current therapies against AD are mostly limited to palliative medications, prompting researchers to investigate more efficient therapeutic approaches for AD, such as stem cell therapy. Recent evidence has proposed that extensive neuronal and synaptic loss and altered adult neurogenesis, which is perceived pivotal in terms of plasticity and network maintenance, occurs early in the course of AD, which exacerbates neuronal vulnerability to AD. Thus, regeneration and replenishing the depleted neuronal networks by strengthening the endogenous repair mechanisms or exogenous stem cells and their cargoes is a rational therapeutic approach. Currently, several stem cell-based therapies as well as stem cell products like exosomes, have shown promising results in the early diagnosis of AD. Objective: This review begins with a comparison between AD and normal aging pathophysiology and a discussion on open questions in the field. Next, summarizing the current stem cell-based therapeutic and diagnostic approaches, we declare the advantages and disadvantages of each method. Also, we comprehensively evaluate the human clinical trials of stem cell therapies for AD. Methodology: Peer-reviewed reports were extracted through Embase, PubMed, and Google Scholar until 2021. Results: With several ongoing clinical trials, stem cells and their derivatives (e.g., exosomes) are an emerging and encouraging field in diagnosing and treating neurodegenerative diseases. Although stem cell therapies have been successful in animal models, numerous clinical trials in AD patients have yielded unpromising results, which we will further discuss.

Huntington’s disease (HD) is a neurodegenerative genetic disorder caused by a CAG repeat expansion in the huntingtin gene. HD causes motor, cognitive, and behavioral dysfunction. Since no existing treatment affects the course of this disease, new treatments are needed. Inflammation is frequently observed in HD patients before symptom onset. Neuroinflammation, characterized by the presence of reactive microglia, astrocytes and inflammatory factors within the brain, is also detected early. However, in comparison to other neurodegenerative diseases, the role of neuroinflammation in HD is much less known. Work has been dedicated to altered microglial and astrocytic functions in the context of HD, but less attention has been given to glial participation in neuroinflammation. This review describes evidence of inflammation in HD patients and animal models. It also discusses recent knowledge on neuroinflammation in HD, highlighting astrocyte and microglia involvement in the disease and considering anti-inflammatory therapeutic approaches.

Recent findings have improved our understanding of the multifactorial nature of AD. While in early asymptomatic stages of AD, increased amyloid-β synthesis and tau hyperphosphorylation play a key role, while in the latter stages of the disease, numerous dysfunctions of homeostatic mechanisms in neurons, glial cells, and cerebrovascular endothelium determine the rate of progression of clinical symptoms. The main driving forces of advanced neurodegeneration include increased inflammatory reactions in neurons and glial cells, oxidative stress, deficiencies in neurotrophic growth and regenerative capacity of neurons, brain insulin resistance with disturbed metabolism in neurons, or reduction of the activity of the Wnt-β catenin pathway, which should integrate the homeostatic mechanisms of brain tissue. In order to more effectively inhibit the progress of neurodegeneration, combination therapies consisting of drugs that rectify several above-mentioned dysfunctions should be used. It should be noted that many widely-used drugs from various pharmacological groups, "in addition" to the main therapeutic indications, have a beneficial effect on neurodegeneration and may be introduced into clinical practice in combination therapy of AD. There is hope that complex treatment will effectively inhibit the progression of AD and turn it into a slowly progressing chronic disease. Moreover, as the mechanisms of bidirectional communication between the brain and microbiota are better understood, it is expected that these pathways will be harnessed to provide novel methods to enhance health and treat AD.

Alcohol consumption during pregnancy and lactation is a widespread preventable cause of neurodevelopmental impairment in newborns. While the harmful effects of gestational alcohol use have been well documented, only recently, the role of paternal preconceptual alcohol consumption (PPAC) prior to copulating has drawn specific epigenetic considerations. Data from human and animal models have demonstrated that PPAC may affect sperm function, eliciting oxidative stress. In newborns, PPAC may induce changes in behavior, cognitive functions, and emotional responses. Furthermore, PPAC may elicit neurobiological disruptions, visuospatial impairments, hyperactivity disorders, motor skill disruptions, hearing loss, endocrine, and immune alterations, reduced physical growth, placental disruptions, and metabolic alterations. Neurobiological studies on PPAC have also disclosed changes in brain function and structure by disrupting the growth factors pathways. In particular, as shown in animal model studies, PPAC alters brain nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF) synthesis and release. This review shows that the crucial topic of lifelong disabilities induced by PPAC and/or gestational alcohol drinking is quite challenging at the individual, societal, and familial levels. Since a nontoxic drinking behavior before pregnancy (for both men and women), during pregnancy, and lactation cannot be established, the only suggestion for couples planning pregnancies is to completely avoid the consumption of alcoholic beverages.

Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease with no specific disease-modifying treatment. β-secretase (BACE1) is considered the potential and rationale target because it is involved in the rate-limiting step, which produces toxic Aβ42 peptides that leads to deposits in the form of amyloid plaques extracellularly, resulting in AD. Objective: This study aims to discuss the role and implications of BACE1 and its inhibitors in the management of AD. Methods: We have searched and collected the relevant quality work from PubMed using the following keywords “BACE1”, BACE2”, “inhibitors”, and “Alzheimer’s disease”. In addition, we included the work which discusses the role of BACE1 in AD and the recent work on its inhibitors. Results: In this review, we have discussed the importance of BACE1 in regulating AD progression and the current development of BACE1 inhibitors. However, the development of a BACE1 inhibitor is very challenging due to the large active site of BACE1. Nevertheless, some of the BACE1 inhibitors have managed to enter advanced phases of clinical trials, such as MK-8931 (Verubecestat), E2609 (Elenbecestat), AZD3293 (Lanabecestat), and JNJ-54861911 (Atabecestat). This review also sheds light on the prospect of BACE1 inhibitors as the most effective therapeutic approach in delaying or preventing AD progression. Conclusion: BACE1 is involved in the progression of AD. The current ongoing or failed clinical trials may help understand the role of BACE1 inhibition in regulating the Aβ load and cognitive status of AD patients.

The caspase family is commonly involved in the pathophysiology of acute brain injury (ABI) through complex apoptotic, pyroptotic, and inflammatory pathways. Current translational strategies for caspase modulation in ABI primarily focus on caspase inhibitors. Because there are no caspase-inhibiting drugs approved for clinical use on the market, the development of caspase inhibitors remains an attractive challenge for researchers and clinicians. Therefore, we conducted the present review with the aim of providing a comprehensive introduction of caspases in ABI. In this review, we summarized the available evidence and potential mechanisms regarding the biological function of caspases. We also reviewed the therapeutic effects of caspase inhibitors on ABI and its subsequent complications. However, various important issues remain unclear, prompting further verification of the efficacy and safety regarding clinical application of caspase inhibitors. We believe that our work will be helpful to further understand the critical role of the caspase family and will provide novel therapeutic potential for ABI treatment.

Background: Along with other canonical systems, the renin-angiotensin system (RAS) has shown important roles in stress. This system is a complex regulatory proteolytic cascade composed of various enzymes, peptides, and receptors. Besides the classical (ACE/Ang II/AT1 receptor) and the counter-regulatory (ACE2/Ang-(1-7)/Mas receptor) RAS axes, evidence indicates that nonclassical components, including Ang III, Ang IV, AT2 and AT4, can also be involved in stress. Objective and Methods: This comprehensive review summarizes the current knowledge on the participation of RAS components in different adverse environmental stimuli stressors, including air jet stress, cage switch stress, restraint stress, chronic unpredictable stress, neonatal isolation stress, and post-traumatic stress disorder. Results and Conclusion: In general, activation of the classical RAS axis potentiates stress-related cardiovascular, endocrine, and behavioral responses, while the stimulation of the counter-regulatory axis attenuates these effects. Pharmacological modulation in both axes is optimistic, offering promising perspectives for stress-related disorders treatment. In this regard, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are potential candidates already available since they block the classical axis, activate the counter-regulatory axis, and are safe and efficient drugs.

The incidence of infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent for coronavirus disease 2019 (COVID-19), has dramatically escalated following the initial outbreak in China, in late 2019, resulting in a global pandemic with millions of deaths. Although the majority of infected patients survive, and the rapid advent and deployment of vaccines have afforded increased immunity against SARS-CoV-2, long-term sequelae of SARS-CoV-2 infection have become increasingly recognized. These include, but are not limited to, chronic pulmonary disease, cardiovascular disorders, and proinflammatory-associated neurological dysfunction that may lead to psychological and neurocognitive impairment. A major component of cognitive dysfunction is operationally categorized as “brain fog” which comprises difficulty concentrating, forgetfulness, confusion, depression, and fatigue. Multiple parameters associated with long-term neuropsychiatric sequelae of SARS-CoV-2 infection have been detailed in clinical studies. Empirically elucidated mechanisms associated with the neuropsychiatric manifestations of COVID-19 are by nature complex, but broad-based working models have focused on mitochondrial dysregulation, leading to systemic reductions of metabolic activity and cellular bioenergetics within the CNS structures. Multiple factors underlying the expression of brain fog may facilitate future pathogenic insults, leading to repetitive cycles of viral and bacterial propagation. Interestingly, diverse neurocognitive sequelae associated with COVID-19 are not dissimilar from those observed in other historical pandemics, thereby providing a broad and integrative perspective on potential common mechanisms of CNS dysfunction subsequent to viral infection. Poor mental health status may be reciprocally linked to compromised immune processes and enhanced susceptibility to infection by diverse pathogens. By extrapolation, we contend that COVID-19 may potentiate the severity of neurological/neurocognitive deficits in patients afflicted by well-studied neurodegenerative disorders, such as Alzheimer's disease and Parkinson’s disease. Accordingly, the prevention, diagnosis, and management of sustained neuropsychiatric manifestations of COVID-19 are pivotal health care directives and provide a compelling rationale for careful monitoring of infected patients, as early mitigation efforts may reduce short- and long-term complications.

Background: Schizophrenia (SZ) is a severe psychiatric disorder typically characterized by multidimensional psychotic syndromes. Electroconvulsive therapy (ECT) is a treatment option for medication-resistant patients with SZ or treating acute symptoms. Although the efficacy of ECT has been demonstrated in clinical use, its therapeutic mechanisms in the brain remain elusive. Objective: This study aimed to summarize brain changes on structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) after ECT. Methods: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was carried out. The PubMed and Medline databases were systematically searched using the following medical subject headings (MeSH): (electroconvulsive therapy OR ECT) AND (schizophrenia) AND (MRI OR fMRI OR DTI OR DWI). Results: This review yielded 12 MRI studies, including 4 with sMRI, 5 with fMRI and 3 with multimodal MRI. Increases in volumes of the hippocampus and its adjacent regions (parahippocampal gyrus and amygdala), as well as the insula and frontotemporal regions, were noted after ECT. fMRI studies found ECT-induced changes in different brain regions/networks, including the hippocampus, amygdala, default model network, salience network and other regions/networks that are thought to highly correlate with the pathophysiologic characteristics of SZ. The results of the correlation between brain changes and symptom remissions are inconsistent. Conclusion: Our review provides evidence supporting ECT-induced brain changes on sMRI and fMRI in SZ and explores the relationship between these changes and symptom remission.