Recent advances in cholinergic mechanisms as reactions to toxicity, stress, and neuroimmune insults

Abstract

This review presents recent studies of the chemical and molecular regulators of acetylcholine (ACh) signaling and the complexity of the small molecule and RNA regulators of those mechanisms that control cholinergic functioning in health and disease. The underlying structural, neurochemical, and transcriptomic concepts, including basic and translational research and clinical studies, shed new light on how these processes inter‐change under acute states, age, sex, and COVID‐19 infection; all of which modulate ACh‐mediated processes and inflammation in women and men and under diverse stresses. The aspect of organophosphorus (OP) compound toxicity is discussed based on the view that despite numerous studies, acetylcholinesterase (AChE) is still a vulnerable target in OP poisoning because of a lack of efficient treatment and the limitations of oxime‐assisted reactivation of inhibited AChE. The over‐arching purpose of this review is thus to discuss mechanisms of cholinergic signaling dysfunction caused by OP pesticides, OP nerve agents, and anti‐cholinergic medications; and to highlight new therapeutic strategies to combat both the acute and chronic effects of these chemicals on the cholinergic and neuroimmune systems. Furthermore, OP toxicity was examined in view of cholinesterase inhibition and beyond in order to highlight improved small molecules and RNA therapeutic strategies and assess their predicted pitfalls to reverse the acute toxicity and long‐term deleterious effects of OPs.image

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

“…Nevertheless, our reactivation study confirms that although both AChE and BChE share the same mechanism of reaction, the structure of OP moiety conjugated at the catalytic serine and difference in residues in the active site direct the specificities of AChE and BChE reactivation and therefore, no single oxime reported in the literature is equally efficient against a variety of OPs or equally potent for both AChE and BChE [29,45]. It is worth mentioning here that, with the design of these uncharged oximes, we joined an endeavor undertaken by several research teams to develop a new generation of CNS-active reactivators [9,[46][47][48][49][50][51][52][53][54][55][56][57].…”

Recent advances in cholinergic mechanisms: A preface for the ISCM2022 special issue

“…In this preface, we highlight the specific contributions at the ISCM2020, starting with a review that span two areas of cholinergic function that are rarely discussed together: the effect of organophosphates (OP) on acetylcholinesterase (AChE) activities and the regulation of cholinergic genes by microRNAs (miRNAs). The authors present novel therapeutic strategies to combat both the acute and chronic effects of these chemicals on the cholinergic tone by improved small molecules and addressing neuroimmune systems by RNA therapeutic strategies to assess their predicted pitfalls in reversing the acute toxicity and avoiding the long-term deleterious effects of OP (Kovarik et al, 2023). This review initiates discussion This is the Preface for the special issue "17th Symposium on Cholinergic Mechanisms (ISCM2022)".…”

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

“…difference in residues in the active site direct the specificities of AChE and BChE reactivation, and therefore, no single oxime, reported in the literature, is equally efficient against a variety of OP and potent for both AChE and BChE[30,50]. It is worth mentioning here that, with design of these uncharged oximes, we joined the endeavour undertaken by several research teams to develop a new generation of CNS-active reactivators[9,[51][52][53][54][55][56][57][58][59][60][61][62][63][64].…”