Anticonvulsant efficacy of antihistamine cyproheptadine in rats exposed to the chemical warfare nerve agent soman

Abstract

Organophosphate compounds, such as soman and sarin, are highly toxic chemical warfare nerve agents that cause a build-up of acetylcholine in synapses and neuromuscular junctions. Current therapies aim to prevent seizures and protect against brain injury following exposure. The present study was designed to evaluate the effectiveness of the antihistamine cyproheptadine in improving survival and controlling seizures in rats exposed to soman. Rats were pretreated with the oxime reactivator HI-6 (125mg/kg, ip) 30min prior to soman exposure (225μg/kg, sc) and then treated with atropine methylnitrate (AMN, 2.0mg/kg, im) 1min after soman. Cyproheptadine (10, 13, 16 or 20mg/kg, ip) was given at one of three time points: 1min after soman intoxication, at the onset of soman-induced seizures or 5min after seizure onset. Control animals were exposed to soman and given an equivalent volume of sterile water instead of cyproheptadine. The incidence of seizures, mortality, neuron counts, neuropathology and apoptosis in specific regions of the brain were evaluated. In animals given HI-6 and AMN the incidence of soman-induced seizure and mortality rate within the first 24h were 100%. When cyproheptadine was given at a dose of 13 or 20mg/kg 1min after soman exposure, the incidence of seizures was reduced from 100% to 13% and 30%, respectively. In addition, cyproheptadine given at 1min after soman exposure increased the survival rate to 100% regardless of dose. When cyproheptadine was administered at seizure onset, seizures were terminated in 100% of the animals at doses above 10mg/kg. The survival rate with cyproheptadine treatment at the onset of seizure was ≥83%. Seizures terminated in ≥75% of the animals that received cyproheptadine 5min after soman-induced seizure onset. When given at 5min after seizure onset the survival rate was 100% at all tested doses of cyproheptadine. The neuropathology scores and the number of TUNEL positive cells in the brain regions examined decreased at all time points and cyproheptadine doses tested. These observations indicate that cyproheptadine treatment can effectively control seizures, improve survival, reduce seizure duration and reduce the number of dying cells in the brain following soman exposure.

Cyproheptadine Regulates Pyramidal Neuron Excitability in Mouse Medial Prefrontal Cortex

“…CPH is known as a typical, first-generation antihistamine [25] with powerful anticholinergic effects [5,26]; however our previous study in cultured mouse cortical neurons demonstrated that CPH enhances I K by activating the r1R/Gi-protein/PKA pathway [9]. In the current study, using a pharmacological antagonist and agonist of r1Rs we confirmed that the effect of CPH on neuronal excitability was also mediated by r1Rs.…”

“…Notably, the structure of CPH is similar to that of antidepressants such as amitriptyline, imipramine, and N-methylamitriptyline [3], while the receptor-binding profile and neuron adaptation of CPH are thought to resemble those of clozapine, indicating a possible use in the treatment of schizophrenia [4]. Although CPH has neurological side-effects, such as sedation and reduced cognitive function [2], it has recently been reported to control seizures, improve survival, reduce seizure duration, and reduce the number of dying cells in the rat brain following exposure to soman [5]. These data suggest that CPH plays a role in the central nervous system, though few studies have explored its possible neurological role and the underlying mechanisms.…”

A primer on nerve agents: what the emergency responder, anesthesiologist, and intensivist needs to know

“…The antihistamine cyproheptadine has been shown to be effective in controlling seizures in experimental models (rat), including reducing the duration of seizures and the number of dying cells in the brain following soman exposure, thus improving overall survival. 72 Human butyrylcholinesterase is a stoichiometric bioscavenger which is being studied as a possible treatment for NA poisoning. It inhibits the NA in the bloodstream and prevents the NA from attacking other enzymes.…”