Current Neuropharmacology - Volume 18, Issue 9, 2020

Blood pressure is a highly controlled cardiovascular parameter that normally guarantees an adequate blood supply to all body tissues. This parameter is mainly regulated by peripheral vascular resistance and is maintained by local mediators (i.e., autacoids), and by the nervous and endocrine systems. Regarding the nervous system, blood pressure can be modulated at the central level by regulating the autonomic output. However, at peripheral level, there exists a modulation by activation of prejunctional monoaminergic receptors in autonomic- or sensory-perivascular fibers. These modulatory mechanisms on resistance blood vessels exert an effect on the release of neuroactive substances from the autonomic or sensory fibers that modify blood pressure. Certainly, resistance blood vessels are innervated by perivascular: (i) autonomic sympathetic fibers (producing vasoconstriction mainly by noradrenaline release); and (ii) peptidergic sensory fibers [producing vasodilatation mainly by calcitonin gene-related peptide (CGRP) release]. In the last years, by using pithed rats, several monoaminergic mechanisms for controlling both the sympathetic and sensory perivascular outflows have been elucidated. Additionally, several studies have shown the functions of many monoaminergic auto-receptors and hetero-receptors expressed on perivascular fibers that modulate neurotransmitter release. On this basis, the present review: (i) summarizes the modulation of the peripheral vascular tone by adrenergic, serotoninergic, dopaminergic, and histaminergic receptors on perivascular autonomic (sympathetic) and sensory fibers, and (ii) highlights that these monoaminergic receptors are potential therapeutic targets for the development of novel medications to treat cardiovascular diseases (with some of them explored in clinical trials or already in clinical use).

Background: NPS belonging to the benzodiazepine (BZD) class, e.g., ‘legal/designer BZDs’/‘research chemicals’, have recently emerged in the drug (mainly online/virtual) market. Objective: While certain NPS belonging to the BZD class possess pharmacological profiles similar to controlled pharmaceutical BZDs, clinical and pharmacological profiles of current emerging BZDs are still not well-described. Therefore, there is a need to increase clinicians’/public health knowledge/awareness, to incentive harm reduction strategies. Method: A comprehensive overview was carried out by using the EMCDDA/EDND database regularly monitored by our research team, by specifically looking at the ‘new BZDs’ so far notified. Furthermore, given the limitation of peer-reviewed data published so far, a nonparticipant multilingual qualitative netnographic study was conducted to obtain further clinical/pharmacological/ toxicological data, including psychonauts’ online trip reports. Results: First designer BZDs appeared as NPS around 2007. So far, 29 designer BZDs have been notified to the EMCDDA, being some of them extremely powerful, also at lower dosages. They are sold as tablets/powder/pellets/capsules/blotters/liquids, at very affordable prices, and variably administered. Some are also sold on the illicit drugmarket as counterfeit forms of traditional BZDs or as either adulterants or diluents in heroin or other synthetic opioids/cannabinoids. Nowadays, there is no guarantee of the quality of designer BZDs composition/purification and, hence, most NPS consumers may be inadvertently exposed to unsafe and harmful compounds. Conclusion: Given the limited information on their pharmacology/toxicity, variations in dosage, onset of effects, combination of substances, potency, and general patient or individual variability, the concomitant use of these substances with other drugs entails several and unpredictable risks.

Background: Cognitive impairment is an adverse reaction of cancer chemotherapy and is likely to affect up to 75% of patients during the treatment and 35% of patients experience it for several months after the chemotherapy. Patients manifest symptoms like alteration in working ability, awareness, concentration, visual-verbal memory, attention, executive functions, processing speed, fatigue and behavioural dysfunctions. Post-chemotherapy, cancer survivors have a reduced quality of life due to the symptoms of chemobrain. Apart from this, there are clinical reports which also associate mood disorders, vascular complications, and seizures in some cases. Therefore, the quality of lifestyle of cancer patients/ survivors is severely affected and only worsens due to the absence of any efficacious treatments. With the increase in survivorship, it’s vital to identify effective strategies, until then only symptomatic relief for chemobrain can be provided. The depressive symptoms were causally linked to the pathophysiological imbalance between the pro and antiinflammatory cytokines. Conclusion: The common causative factor, cytokines can be targeted for the amelioration of an associated symptom of both depression and chemotherapy. Thus, antidepressants can have a beneficial effect on chemotherapy-induced inflammation and cognitive dysfunction via cytokine balance. Also, neurogenesis property of certain antidepressant drugs rationalises their evaluation against CICI. This review briefly glances upon chemotherapy-induced cognitive impairment (CICI), and the modulatory effect of antidepressants on CICI pathomechanisms.

Objectives: The aims of this study were to systematically review the efficacy, acceptability, and tolerability of repetitive transcranial magnetic stimulation (rTMS) combined with antidepressants in the treatment of the first major depressive disorder (MDD) episode. Materials and Methods: The primary efficacious outcome was the pooled mean-endpoint scores of the Hamilton Depression Rating Scale (HAMD). Rates of response, remission rate, overall discontinuation and discontinuation due to adverse events were also evaluated. Search in the Scopus, PubMed, CINAHL, and Cochrane Controlled Trials Register databases for interesting outcomes was carried out in March 2018. Results: A total of 108 randomized patients of two randomized controlled trials were included in this study. The pooled mean- endpoint scores of the HAMD in one, two, and four weeks for rTMS plus antidepressants (citalopram or paroxetine) were greater than that of sham plus the antidepressants. The pooled rates of overall discontinuation and discontinuation rates due to adverse events were not different between the two groups. Conclusion: According to a piece of limited evidence, the high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) could accelerate the antidepressant effect of SSRIs in young patients with a first-episode major depressive disorder. However, the acceptability and tolerability of HF-rTMS in the treatment of such patients are no better than an antidepressant alone. However, further well-defined and large sample-size studies of HF-rTMS combined with an antidepressant in MDD should be carried out to warrant these results.

Glutamate receptor, ionotropic, N-methyl-D-aspartate associated protein 1 (GRINA) is a member of the NMDA receptors (NMDARs) and is involved in several neurological diseases, which governs the key processes of neuronal cell death or the release of neurotransmitters. Upregulation of GRINA has been reported in multiple diseases in human beings, such as major depressive disorder (MDD) and schizophrenia (SCZ), with which the underlying mechanisms remain elusive. In this review, we provide a general overview of the expression and physiological function of GRINA in the central nervous system (CNS) diseases, including stroke, depression ,epilepsy, SCZ, and Alzheimer’s disease (AD).

Alzheimer’s disease is one of the most progressive forms of dementia, ultimately leading to death in aged populations. The major hallmarks of Alzheimer’s disease include deposition of extracellular amyloid senile plaques and intracellular neurofibrillary tangles in brain neuronal cells. Although there are classical therapeutic options available for the treatment of the diseases, however, they provide only a symptomatic relief and do not modify the molecular pathophysiological course of the disease. Recent research advances in Alzheimer’s disease have highlighted the potential role of anti-amyloid, anti-tau, and anti-inflammatory therapies. However, these therapies are still in different phases of pre-clinical/clinical development. In addition, drug repositioning/repurposing is another interesting and promising approach to explore rationalized options for the treatment of Alzheimer’s disease. This review discusses the different aspects of the pathophysiological mechanism involved in the progression of Alzheimer’s disease along with the limitations of current therapies. Furthermore, this review also highlights emerging investigational drugs along with recent drug repurposing approaches for Alzheimer’s disease.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease affecting the elderly. AD is associated with a progressive decline in memory and cognitive abilities, drastic changes in behavioural patterns and other psychiatric manifestations. It leads to a significant decline in the quality of life at personal, household as well as national level. Although AD was described about hundred years back and multiple theories have been proposed, its exact pathophysiology is unknown. There is no cure for AD and the life expectancy of AD patients remains low at 3-9 years. An accurate understanding of the molecular mechanism(s) involved in the pathogenesis of AD is imperative to devise a successful treatment strategy. This review explains and summarises the current understanding of different therapeutic strategies based on various molecular pathways known to date. Different strategies based on anti-amyloid pathology, glutamatergic pathway, anti-tau, neuroprotection through neurotrophic factors and cholinergic neurotransmission have been discussed. Further, the use of anti-inflammatory drugs, nutraceuticals, and dietary interventions has also been explained in the management of AD. It further describes different pharmacological and dietary interventions being used in treating and/or managing AD. Additionally, this article provides a thorough review of the literature for improving the therapeutic paradigm of AD.