Current Neuropharmacology - Volume 19, Issue 4, 2021

The use of neuroprotective agents for stroke is pathogenetically justified, but the translation of the results of preclinical studies of neuroprotectors into clinical practice has been a noticeable failure. One of the leading reasons for these failures is the one-target mechanism of their activity. p-Tyrosol (Tyr), a biophenol, is present in a variety of natural sources, mainly in foods, such as olive oil and wine. Tyr has a wide spectrum of biological activity: antioxidant, stress-protective, anti-inflammatory, anticancer, cardioprotective, neuroprotective and many others. This review analyzes data on the neuroprotective, antioxidant, anti-inflammatory, anti-apoptotic and other kinds of Tyr activity as well as data on the pharmacokinetics of the substance. The data presented in the review substantiate the acceptability of tyr as the basis for the development of a new neuroprotective drug with multitarget activity for the treatment of ischemic stroke. Tyr is a promising molecule for the development of an effective neuroprotective agent for use in ischemic stroke.

In the last few years research into Cannabis and its constituent phytocannabinoids has burgeoned, particularly in the potential application of novel cannabis phytochemicals for the treatment of diverse illnesses related to neurodegeneration and dementia, including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s disease (HD). To date, these neurological diseases have mostly relied on symptomatological management. However, with an aging population globally, the search for more efficient and disease-modifying treatments that could delay or mitigate disease progression is imperative. In this context, this review aims to present state of the art in the research with cannabinoids and novel cannabinoid-based drug candidates that have been emerged as novel promising alternatives for drug development and innovation in the therapeutics of a number of diseases, especially those related to CNS-disturbance and impairment.

Wilson’s disease (WD) is an inherited disease caused by mutations in ATP7B and is characterized by the pathological accumulation of copper in the liver and brain. Common clinical manifestations of WD include a wide range of liver disease and neurological symptoms. In some patients, psychiatric symptoms may be the only manifestation at the time of diagnosis. The clinical features of WD are highly variable and can mimic any disease of internal medicine. Therefore, for unexplained medical diseases, the possibility of WD should not be ignored. Early diagnosis and treatment can improve the prognosis of WD patients and reduce disability and early death. Gene sequencing is becoming a valuable method to diagnose WD, and if possible, all WD patients and their siblings should be genetically sequenced. Copper chelators including D-penicillamine, trientine, and dimercaptosuccinic acid can significantly improve the liver injury and symptoms of WD patients but may have a limited effect on neurological symptoms. Zinc salts may be more appropriate for the treatment of asymptomatic patients or for the maintenance treatment of symptomatic patients. High-quality clinical trials for the drug treatment of WD are still lacking, therefore, individualized treatment options for patients are recommended. Individualized treatment can be determined based on the clinical features of the WD patients, efficacy and adverse effects of the drugs, and the experience of the physician. Liver transplantation is the only effective method to save patients with acute liver failure or with severe liver disease who fail drug treatment.

Nur77 belongs to the NR4A subgroup of the nuclear receptor superfamily. Unlike other nuclear receptors, a natural ligand for Nur77 has not been identified yet. However, a few small molecules can interact with this receptor and induce a conformational change to mediate its activity. The expression and activation of Nur77 can be rapidly increased using various physiological and pathological stimuli. In vivo and in vitro studies have demonstrated its regulatory role in tissues and cells of multiple systems by means of participation in cell differentiation, apoptosis, metabolism, mitochondrial homeostasis, and other processes. Although research on Nur77 in the pathophysiology of the central nervous system (CNS) is currently limited, the present data support the fact that Nur77 is involved in many neurological disorders such as stroke, multiple sclerosis, Parkinson’s disease. This indicates that activation of Nur77 has considerable potential in treating these diseases. This review summarizes the regulatory mechanisms of Nur77 in CNS diseases and presents available evidence for its potential as targeted therapy, especially for cerebrovascular and inflammationrelated CNS diseases.

Alzheimer’s disease (AD), recognized as the most common neurodegenerative disorder, is clinically characterized by the presence of extracellular beta-amyloid (Aβ) plaques and by intracellular neurofibrillary tau tangles, accompanied by glial activation and neuroinflammation. Increasing evidence suggests that self-misfolded proteins stimulate an immune response mediated by glial cells, inducing the release of inflammatory mediators and the recruitment of peripheral macrophages into the brain, which in turn aggravate AD pathology. The present review aims to update the current knowledge on the role of autoimmunity and neuroinflammation in the pathogenesis of the disease, indicating a new target for therapeutic intervention. We mainly focused on the NLRP3 microglial inflammasome as a critical factor in stimulating innate immune responses, thus sustaining chronic inflammation. Additionally, we discussed the involvement of the NLRP3 inflammasome in the gut-brain axis. Direct targeting of the NLRP3 inflammasome and the associated receptors could be a potential pharmacological strategy since its inhibition would selectively reduce AD neuroinflammation.

Temozolomide (TMZ), an oral alkylating prodrug which delivers a methyl group to purine bases of DNA (O6-guanine; N7-guanine and N3-adenine), is frequently used together with radiotherapy as part of the first-line treatment of high-grade gliomas. The main advantages are its high oral bioavailability (almost 100% although the concentration found in the cerebrospinal fluid was approximately 20% of the plasma concentration of TMZ), its lipophilic properties, and small size that confer the ability to cross the blood-brain barrier. Furthermore, this agent has demonstrated activity not only in brain tumors but also in a variety of solid tumors. However, conventional therapy using surgery, radiation, and TMZ in glioblastoma results in a median patient survival of 14.6 months. Treatment failure has been associated with tumor drug resistance. This phenomenon has been linked to the expression of O6-methylguanine-DNA methyltransferase, but the mismatch repair system and the presence of cancer stem-like cells in tumors have also been related to TMZ resistance. The understanding of these mechanisms is essential for the development of new therapeutic strategies in the clinical use of TMZ, including the use of nanomaterial delivery systems and the association with other chemotherapy agents. The aim of this review is to summarize the resistance mechanisms of TMZ and the current advances to improve its clinical use.

There are several studies investigating the effects of risperidone on autism, but many of these studies are contradictory or inconclusive. This systematic review and meta-analysis investigated the effects of risperidone on five domains of the Aberrant Behaviour Checklist (ABC) scale on Autism Spectrum Disorder (ASD), as well as weight gain and waist circumference. The protocol for the present systematic review and meta-analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO). For this study, we analysed articles (2,459), selecting them according to the PICOS strategy (Population, Intervention, Comparison, Outcome, Study design). Although risperidone is effective for the treatment of lethargy and inadequate speech, concerns about the association between weight gain, waist circumference and risperidone require a need for evaluation of the risk-benefit ratio in its use. There was a significant association between weight gain, waist circumference and risperidone. In conclusion, it was possible to suggest the efficacy of risperidone for the treatment of lethargy and inadequate speech. Finally, we emphasize that the risk-benefit in its use should be evaluated (Protocol number CRD42019122316).

Pain is a distressing but fundamental manifestation that prepares the body for potentially detrimental stimuli while ensuring its protection. Plant and animal products have traditionally been used to relieve pain for centuries. However, no attempt has been made to compile a single report of plant and animal products possessing analgesic properties. This review enadeavours to recover data from published articles to establish a collective literature review on folk remedies from plant and animal sources used as analgesics and in the treatment of pain-related conditions, identifying gaps in existing knowledge and future works. Relevant information was systematically retrieved using the PRISMA method. In this review, in total, 209 plants were found to be either used raw or prepared by decoctions or maceration. Administration was either oral or topical, and they were predominantly used in Asian countries. In vivo studies of plants with analgesic properties, which were tested using different methods including acetic-induced writhing test, hotplate test, tail-flick test, and formalin-induced pain test, were compiled. Animal products with analgesic properties were obtained mainly from compounds present in venom; their bioactive compounds were also identified. In the literature search, certain gaps were noted, which could be reviewed in future studies. For instance, there was a disparity of information regarding the traditional uses of medicinal plants. In this review, an attempt was made to critically assess and describe the pharmacological properties and bioactive composition of indigenous plants, some animal species, and animal venom by scrutinizing databases and looking for published articles. Therefore, it can be concluded that the compounds obtained from these sources can serve as important ingredients in therapeutic agents to alleviate pain once their limitations are assessed and improved upon. In the literature search, certain gaps were noted, which could be reviewed in future studies.