(-)-Phenserine Attenuates Soman-Induced Neuropathology

Abstract

Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy.

Alpha-Linolenic Acid-Induced Increase in Neurogenesis is a Key Factor in the Improvement in the Passive Avoidance Task After Soman Exposure

“…All surgeries and injections were standardized to avoid any additional variables. Sterile heparin-saline was injected using a standardized schedule to prevent clot formation within the catheter (Chen et al 2014;Pan et al 2012a, b).…”

(−)‐Phenserine tartrate (PhenT) as a treatment for traumatic brain injury

“…It proved well tolerated in human studies (645 subjects for up to 1 year) and demonstrated a signal of efficacy in AD . Notably, recent studies have demonstrated a far more interesting pharmacological action, in that it inhibits programmed neuronal cell death (PNCD, eg, apoptosis/autophagy) across multiple cellular and animal neuronal injury models at clinically translatable doses . Detailed within our results described below, across preclinical neuronal injury models particularly in mTBI and modTBI, PhenT mitigates impairments in synaptic integrity, neuroinflammation and inhibits gene pathways leading to AD .…”

“…This was appraised by multiple complimentary techniques, including quantitative TUNEL, NeuN, and FJC staining, as well as Western blot quantification of pro‐apoptotic (activated caspase 3) and antiapoptotic (Bcl‐2 and BDNF) protein levels. In addition to these reviewed studies, PhenT has presented PNCD inhibiting actions in rodents challenged with toxic doses of soman, reducing its lethality and, importantly, protecting the brain from neuronal loss . In evaluating mechanisms in the soman study, PhenT was found to regulate a core set of neuroprotective genes termed 'activity‐regulated inhibitor of death' (AID) genes, as well as genes impacting neuroinflammatory pathways.…”

“…All achieve brain levels that vary between 7‐ and 1.25‐fold higher than concomitant plasma ones (Figure ) and, in concentration‐dependent relationships (EC 50 s = 26 to 100 nmol/L), produce a range of pharmacological benefits relevant to TBI and AD neuropathologies. Notably, PhenT provides protection from PNCD, anti‐inflammatory, and antioxidative stress; its actions include augmenting neurotrophic factor levels, brain acetylcholine levels, and neuronal stem cell survival and differentiation, as well as inhibiting APP and Aβ generation, as recently reviewed . PhenT is well tolerated across preclinical animal models, and in human studies (645 subjects) for up to 1 year, positively impacted markers of efficacy in AD; importantly, it also mitigates multiple sequelae instigated by TBI and brain injury …”

Mechanism and Clinical Importance of Respiratory Failure Induced by Anticholinesterases

“…It is generally accepted that soman and other centrallyacting AChE inhibitors via cholinoceptor hyperstimulation start a vicious circle that ends up with glutamatergic excitatory discharges that clinically manifest themselves as seizures and leave the survivors with serious brain damage (45,46). It is not clear what the relation between the onset of seizures and the occurrence of respiratory depression is in soman-poisoned animals, since most of the cited experiments have been performed under urethane anaesthesia (47).…”