Current Reviews in Clinical and Experimental Pharmacology - Volume 18, Issue 3, 2023

The neurobiology drug discovery landscape has transformed over the past decade or so by the discovery of allosteric modulators of receptor superfamilies. A wide range of physiological reactions can occur in response to a limited number of neurotransmitters. This review provides an update on physiological features of the receptors and the signaling pathways that are generated in response to neuroreceptor activation that allow the explanation of this vast array of neurotransmitter responses. Primarily based upon structure, receptors in the nervous system can be classified into four groups: Gprotein coupled receptors, ligand-gated receptors, enzyme-linked receptors, and nuclear receptors. With a particular emphasis on the central nervous system, i.e., brain, spinal cord, and optic nerves, we identify the neuroreceptors, their endogenous agonists, antagonists, sites of expression within the nervous system, current neuropharmacological clinical use, and potential for new drug discovery. New molecular approaches and advances in our knowledge of neuronal communication in processes involved in development, functioning and disorders of the nervous system combined with opportunities to re-purpose existing drugs for new indications continue to highlight the exciting opportunities to improve human health.

Glucocorticoid steroids play cardinal roles during the life span of an individual, modulating almost all aspects of the physiology, including the metabolism of carbohydrates, lipids and amino acids, as well as the immune response, neurological biology, stress adaptation, apoptosis, cell division, cell fate, inflammatory responses, etc. Glucocorticoids exert their biological effects by activation of the glucocorticoid receptor (GR), a bona fide ligand-activated transcription factor belonging to the nuclear receptor superfamily. The GR is expressed in virtually all cells of the human body showing isoformic versions and also transcription variants. GR forms oligomeric heterocomplexes that include the 90-kDa heat-shock protein (Hsp90) as an essential hub of the chaperone oligomer. The nature of chaperones associated with this heterocomplex is responsible for the modulation of the subcellular localization of the GR and its biological actions in a given tissue or cell type. In this sense, the discovery that immunophilins containing tetratricopeptide repeats (TPR) domains are responsible for the GR cytoplasmic transport mechanism and the nuclear retention half-time of the receptor opened new trends in our understanding of its complex mechanism of action. Because the properties of GR ligands influence these protein-protein interactions, specific steroid•receptor complexes may confer the GR different features providing new therapeutic opportunities to manage the disease. In this article, we analyze multiple aspects of the GR mechanism of action, some properties of the GR isoforms, and the latest findings revealing the roles of Hsp90-binding immunophilins to manage the glucocorticoid biological response.

Background: Deficits in cognitive functions are observed in various diseases. The term “nootropics” refers to the compounds that increase mental functions, including memory, motivation, concentration and attention. Given the complexity and vastness of the processes involved in cognition, developing an appropriate animal model for the screening of nootropic agents still remains a daunting task. Objectives: This review attempts to elicit the current trends in the animal models being used for screening of nootropic agents and effectively use this knowledge to improve prospects embarking on this area of research. Methods: Electronic searches were carried out on PubMed using the keywords “nootropic agents”[MeSH Term] OR “nootropic drugs” [MeSH Term] AND “animal model” [MeSH Term] OR “animal model, experimental” [MeSH Term]. All relevant studies from 2016 to 31st August, 2021, were then reviewed to meet the stated objective. Results: The most commonly used disease model for screening of nootropic agents was found to be the animal model of Alzheimer’s disease. Disease models of vascular dementia or stroke, depression or anxiety, schizophrenia, epilepsy or seizure, diabetes and traumatic brain injury, among others, have also been used. There exists a wide variety of behavioral tests to assess cognition. Conclusion: Since a variety of etiologies can affect cognitive processes. Hence, a nootropic agent may be screened in a variety of disease models. The most widely used and appropriate method to assess cognition would be by combining the behavioral and biochemical assays so that a more comprehensive profile of the nootropic effects of a drug can be elicited.

Background: P2Y12 inhibitors have been widely used as an alternative to aspirin in clinical practice for secondary stroke prevention. We aimed to compare the efficiency and safety of P2Y12 inhibitors and aspirin for stroke prevention in patients with previous stroke or transient ischaemic attack (TIA). Methods: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. All randomized trials that compared P2Y12 inhibitors with aspirin among patients with stroke were included. The primary efficacy outcomes of our meta-analysis included stroke, vascular events, and all-cause death. The primary safety outcome was minor or major bleeding events. Results: The search identified 4 randomized clinical trials comparing P2Y12 inhibitors with aspirin for secondary stroke prevention that collectively enrolled 24508 patients (12253 received P2Y12 inhibitor and 12255 received aspirin). Pooled results from the random-effects model showed that there were no significant differences in the risk of any stroke (OR 0.90 (0.78-1.04); I²=56.9%), vascular event (OR 0.91 (0.74-1.13); I²=78.3%), all-cause death (OR 0.98 (0.83-1.17); I²=0%), or minor or major bleeding (OR 1.13 (0.70-1.82); I²=79%) among patients who received a P2Y12 inhibitor or aspirin. P2Y12 inhibitors were associated with a significantly lower risk of recurrent ischaemic stroke (OR 0.84 (0.73- 0.96); I²=25%) than aspirin. Conclusion: This meta-analysis suggests that P2Y12 inhibitors are more effective than aspirin in preventing recurrent ischaemic stroke among ischaemic stroke patients despite the absence of any effect on a new ischaemic or haemorrhagic stroke, a new clinical vascular event, all-cause death, and major or minor bleeding events.

Background: Autosomal dominant polycystic kidney disease (ADPKD) may coexist with other genetic disorders, such as tuberous sclerosis, when deletion in TSC2/PKD1 genes occurs. Recently, the effect of tolvaptan has been explored in ADPKD patients alone, but its safety and efficacy on TSC2/PKD1 contiguous gene syndrome are unknown. Case Presentation: This report describes the case of an asymptomatic patient with TSC2/PKD1 contiguous gene syndrome that fulfills the imaging criteria for initiating the treatment with tolvaptan. After twelve months, the patient did not exhibit severe adverse effects and blood pressure control improved. Conclusion: In this TSC2/PKD1 contiguous gene syndrome single case report, tolvaptan was safe and well-tolerated. More extensive experimental studies are needed to deeply understand the therapeutic implications of vasopressin V2-receptor inhibition in the TSC2/PKD1 contiguous gene syndrome patients.