**6. Excess ACh**

Overall, excess ACh in synaptic cleft results in overstimulation of nicotinic or muscarinic receptors, which in turn, result in activation of the glutamatergic system and the development of seizures [24]. Other central effects include cognitive impairments (discussed below), as well as motivational, arousal and attentional problems. Indeed, this is the mechanism of toxicity induced by organophosphorus compounds, including nerve gases, whereby inhibition of AChE causes accumulation of ACh in the synapse. Aside from central site, peripheral accumulation of ACh may lead to dysregulation in heart contraction, blood pressure, decrease heart rate, increase glandular secretion including saliva, tear, sweat and digestive juices, increase in urination frequency, visual disturbance and importantly, inhibition of muscle contraction due to nicotinic receptor desensitization. Generation of reactive oxygen species (ROS), neuroinflammation are other causes of neuropathies.

Atropine, a mAChR antagonist, is the primary antidote used to counter organophosphate poisoning. However, specific cases of inhibition of nAChRs by atropine have also been reported [25]. In order to overcome the effect of organophosphates on nicotinic receptors, which can result in muscle weakness, fasciculation and paralysis, pralidoxime (2-PAM) also should be given, as 2-PAM tends to reactivate AChE. Interestingly, 2-PAM may also have some muscarinic inhibition, although such effect is not clinically significant and hence necessity of co-administration with atropine [25].

In addition, patients with seizures are given benzodiazepine (BZ), which stimulate GABAAR. Since BZs are of limited efficacy in overall organophosphate toxicity, it is suggested that antagonizing the hyperactivity of the glutamatergic system could provide an even more efficacious approach in protecting the brain from permanent damage. This may be further helped by adding an anticholinergic agent [24].
