Potential pharmacological strategies for the improved treatment of organophosphate-induced neurotoxicity

Abstract

Organophosphates (OP) are highly toxic compounds that cause cholinergic neuronal excitotoxicity and dysfunction by irreversible inhibition of acetylcholinesterase, resulting in delayed brain damage. This delayed secondary neuronal destruction, which arises primarily in the cholinergic areas of the brain that contain dense accumulations of cholinergic neurons and the majority of cholinergic projection, could be largely responsible for persistent profound neuropsychiatric and neurological impairments such as memory, cognitive, mental, emotional, motor, and sensory deficits in the victims of OP poisoning. The therapeutic strategies for reducing neuronal brain damage must adopt a multifunctional approach to the various steps of brain deterioration: (i) standard treatment with atropine and related anticholinergic compounds; (ii) anti-excitotoxic therapies to prevent cerebral edema, blockage of calcium influx, inhibition of apoptosis, and allow for the control of seizure; (iii) neuroprotection by aid of antioxidants and N-methyl-d-aspartate (NMDA) antagonists (multifunctional drug therapy), to inhibit/limit the secondary neuronal damage; and (iv) therapies targeting chronic neuropsychiatric and neurological symptoms. These neuroprotective strategies may prevent secondary neuronal damage in both early and late stages of OP poisoning, and thus may be a beneficial approach to treating the neuropsychological and neuronal impairments resulting from OP toxicity.

Markers and Biomarkers of Endothelium: When Something Is Rotten in the State

“…In spite of recent advances in the therapeutic treatment of OP poisonings, they usually proceed with predominance of a heavy cholinergic crisis, and even in the case of survival of a victim, delayed pathologies are often observed: the so-called "intermediate syndrome"; OP-induced distal sensorimotor axonophaty; symptoms of vegetative changes of the circulatory system; the CNS "microorganic disorders" with unknown ethiology, and so forth [190][191][192]. Because AChE is the main target of OPs, the principles of existing therapy of acute poisoning are converged to elimination of effects of AChE inhibition by OPs, that is, administration of cholinolytics (e.g., atropin), reactivators of AChE (oximes), and anticonvulsant drugs (agonists of GABA-and antagonists of glutamate receptors); as a preventive means before the alleged poisoning, reversible AChE inhibitors can be used (e.g., pyridostigmine) [193,194]. Mechanistic studies are reduced to revealing interactions of OPs with molecular targets in nerve cells.…”

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication

“…Secondary neuronal toxicity during severe acute OP intoxication results in brain damage (Kaur et al 2014). We tested the zebrafish model using three groups of compounds that target key components of the pathophysiological pathways of secondary neuronal toxicity: glutamate antagonists, dual-function NMDA receptor and AChR antagonists, and anti-inflammatory drugs.…”

“…Then, a cascade of downstream events occurs, resulting in secondary neuronal toxicity. The release of excitatory amino acids (EAAs), such as glutamate and aspartate, and the activation of the N -methyl- d -aspartate (NMDA) receptors promote intracellular Ca 2+ influx, which can activate different lipases, proteases, endonucleases, kinases or phosphatases and result in severe brain damage (Kaur et al 2014). The generation of reactive oxygen or nitrogen species may also play an important role in the development of neuroinflammation and cellular death that are found in severe acute OP intoxication (Eisenkraft et al 2013; Pena-Llopis 2005).…”

Possible role for anisodamine in organophosphate poisoning

“…A follow‐up study has shown some change towards faster dosing protocols, but the variability still exists (Connors et al , ), which may be one of the reasons why atropinization is difficult to attain in some severely poisoned patients (Kaur et al ., ; Iyer et al ., ). Recent reviews covering novel and alternative ways for treating OP poisoning (Kaur et al ., ; Iyer et al ., ) have supported the Wang et al . (2014a,b) proposal that anisodamine can be used as a safe adjunct or substitute to atropine, for cases where atropinization is difficult to achieve.…”

“…A comparison of existing atropine treatment protocols in OP poisoning has shown that the protocols are poorly evidence-based, highly variable between published sources, and most of them are too slow to achieve the desired atropinization dose in time (Eddleston et al, 2004). A follow-up study has shown some change towards faster dosing protocols, but the variability still exists (Connors et al, 2014), which may be one of the reasons why atropinization is difficult to attain in some severely poisoned patients (Kaur et al, 2014;Iyer et al, 2015). Recent reviews covering novel and alternative ways for treating OP poisoning (Kaur et al, 2014;Iyer et al, 2015) have supported the Wang et al (2014a,b) proposal that anisodamine can be used as a safe adjunct or substitute to atropine, for cases where atropinization is difficult to achieve.…”