Current Neuropharmacology - Volume 20, Issue 4, 2022

Uncoupling protein 2 (UCP2) is a mitochondrial protein that acts as an anion carrier. It is involved in the regulation of several processes, including mitochondrial membrane potential, generation of reactive oxygen species within the inner mitochondrial membrane and calcium homeostasis. UCP2 expression can be regulated at different levels: genetic (gene variants), transcriptional [by peroxisome proliferator-activated receptors (PPARs) and microRNAs], and post-translational. Experimental evidence indicates that activation of UCP2 expression through the AMPK/PPAR-α axis exerts a protective effect toward renal damage and stroke occurrence in an animal model of ischemic stroke (IS) associated with hypertension. UCP2 plays a key role in heart diseases (myocardial infarction and cardiac hypertrophy) and metabolic disorders (obesity and diabetes). In humans, UCP2 genetic variants (-866G/A and Ala55Val) associate with an increased risk of type 2 diabetes mellitus and IS development. Over the last few years, many agents that modulate UCP2 expression have been identified. Some of them are natural compounds of plant origin, such as Brassica oleracea, curcumin, berberine and resveratrol. Other molecules, currently used in clinical practice, include anti-diabetic (gliptin) and chemotherapeutic (doxorubicin and taxol) drugs. This evidence highlights the relevant role of UCP2 for the treatment of a wide range of diseases, which affect the national health systems of Western countries. We will review current knowledge on the physiological and pathological implications of UCP2 with particular regard to cardiovascular and metabolic disorders and will focus on the available therapeutic approaches affecting UCP2 level for the treatment of human diseases.

Alzheimer’s disease (AD) is one of the major reasons for 60-80% cases of senile dementia occurring as a result of the accumulation of plaques and tangles in the hippocampal and cortical neurons of the brain leading to neurodegeneration and cell death. The other pathological features of AD comprise abnormal microvasculature, network abnormalities, interneuronal dysfunction, increased β-amyloid production and reduced clearance, increased inflammatory response, elevated production of reactive oxygen species, impaired brain metabolism, hyperphosphorylation of tau, and disruption of acetylcholine signaling. Among all these pathologies, Mitochondrial Dysfunction (MD), regardless of it being an inciting insult or a consequence of the alterations, is related to all the associated AD pathologies. Observed altered mitochondrial morphology, distribution and movement, increased oxidative stress, dysregulation of enzymes involved in mitochondrial functioning, impaired brain metabolism, and impaired mitochondrial biogenesis in AD subjects suggest the involvement of mitochondrial malfunction in the progression of AD. Here, various pre-clinical and clinical evidence establishing MD as a key mediator in the progression of neurodegeneration in AD are reviewed and discussed with an aim to foster future MD based drug development research for the management of AD.

Psychiatric drugs have primacy for off-label prescribing. Among those, selective serotonin reuptake inhibitors (SSRIs) are highly versatile and, therefore, widely prescribed. Moreover, they are commonly considered as having a better safety profile compared to other antidepressants. Thus, when it comes to off-label prescribing, SSRIs rank among the top positions. In this review, we present the state of the art of off-label applications of selective serotonin reuptake inhibitors, ranging from migraine prophylaxis to SARS-CoV-2 antiviral properties. Research on SSRIs provided significant evidence in the treatment of premature ejaculation, both with the on-label dapoxetine 30 mg and the off-label paroxetine 20 mg. However, other than a serotoninergic syndrome, serious conditions like increased bleeding rates, hyponatremia, hepatoxicity, and post-SSRIs sexual dysfunctions, are consistently more prominent when using such compounds. These insidious side effects might be frequently underestimated during common clinical practice, especially by nonpsychiatrists. Thus, some points must be addressed when using SSRIs. Among these, a psychiatric evaluation before every administration that falls outside the regulatory agencies-approved guidelines has to be considered mandatory. For these reasons, we aim with the present article to identify the risks of inappropriate uses and to advocate the need to actively boost research encouraging future clinical trials on this topic.

Alzheimer’s disease (AD) is the only leading cause of death for which no disease-modifying therapy is currently available. Over the past decade, a string of disappointing clinical trial results has forced us to shift our focus to the preclinical stage of AD, which represents the most promising therapeutic window. However, the accurate diagnosis of preclinical AD requires the presence of brain β- amyloid deposition determined by cerebrospinal fluid or amyloid-positron emission tomography, significantly limiting routine screening and diagnosis in non-tertiary hospital settings. Thus, an easily accessible marker or tool with high sensitivity and specificity is highly needed. Recently, it has been discovered that individuals in the late stage of preclinical AD may not be truly “asymptomatic” in that they may have already developed subtle or subjective cognitive decline. In addition, advances in bloodderived biomarker studies have also allowed the detection of pathologic changes in preclinical AD. Exosomes, as cell-to-cell communication messengers, can reflect the functional changes of their source cell. Methodological advances have made it possible to extract brain-derived exosomes from peripheral blood, making exosomes an emerging biomarker carrier and liquid biopsy tool for preclinical AD. The eye and its associated structures have rich sensory-motor innervation. In this regard, studies have indicated that they may also provide reliable markers. Here, our report covers the current state of knowledge of neuropsychological and eye tests as screening tools for preclinical AD and assesses the value of blood and brain-derived exosomes as carriers of biomarkers in conjunction with the current diagnostic paradigm.

Major depressive disorder is the most common mental disorder with significant economic burden and limited treatments. Acupuncture has emerged as a promising non-pharmacological treatment for reducing depressive symptoms. However, the potential mechanisms and clinical effectiveness of acupuncture are not fully understood. This review aimed to: (1) summarize the available evidence on the mechanisms and clinical effectiveness of acupuncture for depression, and then (2) compare with pharmacological interventions, guiding future studies. Studies with animal models of depression and patients have shown that acupuncture could increase hippocampal and network neuroplasticity and decrease brain inflammation, potentially to alleviating depressive disorders. Overall clinical studies indicated that acupuncture could relieve primary depression, particularly milder cases, and was helpful in the management of post-stroke depression, pain-related depression, and postpartum depression both as an isolated and adjunct treatment. It was emphasized that acupuncture combined with antidepressant pharmacological treatment not only enhanced the improvement of primary and secondary depressive symptoms but also reduced the side effects of the medical treatment, which is the main cause for high dropout rates with drug treatment. In summary, substantial evidence from animal and human researches supported the beneficial effect of acupuncture in depression. However, most clinical trials of acupuncture were small, and it is unclear whether their findings can be generalized, so more studies are needed.

Brain ischemia, also known as ischemic stroke, occurs when there is a lack of blood supply into the brain. When an ischemic insult appears, both neurons and glial cells can react in several ways that will determine the severity and prognosis. This high heterogeneity of responses has been a major obstacle in developing effective treatments or preventive methods for stroke. Although white matter pathophysiology has not been deeply assessed in stroke, its remodelling can greatly influence the clinical outcome and the disability degree. Oligodendrocytes, the unique cell type implied in CNS myelination, are sensible to ischemic damage. Loss of myelin sheaths can compromise axon survival, so new Oligodendrocyte Precursor Cells are required to restore brain function. Stroke can, therefore, enhance oligodendrogenesis to regenerate those new oligodendrocytes that will ensheath the damaged axons. Given that myelination is a highly complex process that requires coordination of multiple pathways such as Sonic Hedgehog, RTKs or Wnt/β-catenin, we will analyse new research highlighting their importance after brain ischemia. In addition, oligodendrocytes are not isolated cells inside the brain, but rather form part of a dynamic environment of interactions between neurons and glial cells. For this reason, we will put some context into how microglia and astrocytes react against stroke and influence oligodendrogenesis to highlight the relevance of remyelination in the ischemic brain. This will help to guide future studies to develop treatments focused on potentiating the ability of the brain to repair the damage.

Background: Phthalates are widely used in the plastics industry. Di-2-Ethylhexyl Phthalate (DEHP) is one of the most important phthalate metabolites that disrupt the function of endocrine glands. Exposure to DEHP causes numerous effects on animals, humans, and the environment. Low doses of DEHP increase neurotoxicity in the nervous system that has arisen deep concerns due to the widespread nature of DEHP exposure and its high absorption during brain development. Objective: In this review article, we evaluated the impacts of DEHP exposure from birth to adulthood on neurobehavioral damages. Then, the possible mechanisms of DEHP-induced neurobehavioral impairment were discussed. Methodology: Peer-reviewed articles were extracted through Embase, PubMed, and Google Scholar till the year 2021. Results: The results showed that exposure to DEHP during pregnancy and infancy leads to memory loss and irreversible nervous system damage. Conclusion: Overall, it seems that increased levels of oxidative stress and inflammatory mediators possess a pivotal role in DEHP-induced neurobehavioral impairment.

Background: As the World faces unprecedented pandemic caused by SARS-CoV-2 virus, repositioning of existing drugs to treatment of COVID-19 disease is urgently awaited, provided that high quality scientific evidence supporting safety and efficacy in this new indication is gathered. Efforts concerning drugs repositioning to COVID-19 were mostly focused on antiviral drugs, or drugs targeting the late phase of the disease. Methods: Based on published research, the pharmacological activities of fluvoxamine and amantadine, two well-known drugs widely used in clinical practice for psychiatric and neurological diseases, respectively, have been reviewed, with a focus on their potential therapeutic importance in the treatment of COVID-19. Results: Several preclinical and clinical reports were identified suggesting that these two drugs might exert protective effects in the early phases of COVID-19. Conclusion: Preclinical and early clinical evidence are presented indicating that these drugs hold promise to prevent COVID-19 progression when administered early during the course of infection.

The microtubule skeleton plays an essential role in nerve cells as the most important structural determinant of morphology and as a highway for axonal transport processes. Many neurodegenerative diseases are characterized by changes in the structure and organization of microtubules and microtubule-regulating proteins such as the microtubule-associated protein tau, which exhibits characteristic changes in a whole class of diseases collectively referred to as tauopathies. Changes in the dynamics of microtubules appear to occur early under neurodegenerative conditions and are also likely to contribute to age-related dysfunction of neurons. Thus, modulating microtubule dynamics and correcting impaired microtubule stability can be a useful neuroprotective strategy to counteract the disruption of the microtubule system in disease and aging. In this article, we review current microtubule- directed approaches for the treatment of neurodegenerative diseases with microtubules as a drug target, tau as a drug target, and post-translational modifications as potential modifiers of the microtubule system. We discuss limitations of the approaches that can be traced back to the rather unspecific mechanism of action, which causes undesirable side effects in non-neuronal cell types or which are due to the disruption of non-microtubule-related interactions. We also develop some thoughts on how the specificity of the approaches can be improved and what further targets could be used for modulating substances.

Poloxamer 188 (P188) is an FDA-approved biocompatible block copolymer composed of repeating units of Poly(Ethylene Oxide) (PEO) and poly(propylene oxide) (PPO). Due to its amphiphilic nature and high Hydrophile-Lipophile Balance (HLB) value of 29, P188 is used as a stabilizer/emulsifier in many cosmetics and pharmaceutical preparations. While the applications of P188 as an excipient are widely explored, the data on the pharmacological activity of P188 are scarce. Notably, the neuroprotective potential of P188 has gained a lot of interest. Therefore, this systematic review is aimed at summarizing evidence of neuroprotective potential of P188 in CNS disorders. The PRISMA model was used, and five databases (Google Scholar, Scopus, Wiley Online Library, ScienceDirect, and PubMed) were searched with relevant keywords. The search resulted in 11 articles, which met the inclusion criteria. These articles described the protective effects of P188 on traumatic brain injury or mechanical injury in cells, neurotoxicity, Parkinson’s disease, Amyotrophic lateral sclerosis (ALS), and ischemia/ reperfusion injury from stroke. All the articles were original research in experimental or pre-clinical stages using animal models or in vitro systems. The reported activities demonstrated the potential of P188 as a neuroprotective agent in improving CNS conditions such as neurodegeneration.

Background: GHB (gamma-hydroxybutyric acid; sodium oxybate) is a general anaesthetic that is clinically used for the treatment of narcolepsy, cataplexy, alcohol withdrawal and alcohol relapse prevention. In addition, GHB is recreationally used. Most clinical and recreational users regard GHB as an innocent drug devoid of adverse effects, despite its high dependence potential and possible neurotoxic effects. At high doses, GHB may lead to a comatose state. This paper systematically reviews possible cognitive impairments due to clinical and recreational GHB use. Methods: PubMed and PsychINFO were searched for literature data about the acute and residual cognitive deficits following GHB use. This review is conducted using the PRISMA protocol. Results: A total of 43 reports covering human and animal data on GHB-induced cognitive impairments were eligible and reviewed. This systematic review found no indication for cognitive impairments after clinical GHB use. However, it supports the view that moderate GHB use may result in acute short-term cognitive impairments, whereas regular high-dose GHB use and/or multiple GHB-induced comas are probably neurotoxic resulting in long-term residual cognitive impairments. Conclusion: These results emphasize the need for awareness among clinicians and recreational users to minimize negative health consequences of recreational GHB use, particularly when high doses are used and GHB-induced comas occur.