Exposure to nerve agents such as sarin and soman causes an array of toxic effects, including hypersecretions, fasciculations, tremors, convulsions and death within minutes due to respiratory distress . These toxic effects are mainly due to hyperactivity of the cholinergic system as a result of acetylcholinesterase (AChE) inhibition and the subsequent increase of the neurotransmitter acetylcholine at central and peripheral sites. The potential for exposure to nerve agents in a real world situation is likely to occur as a result of military operations, a terrorist incident, or accidental exposure, including demilitarization of weaponized material. Recent alleged use of nerve agent, sarin on civilian’s in Syria indicates their potential threat to civilian and military population. Use of chemical weapons (CW) still remains a major concern despite the efforts of the Organization for Prohibition of Chemical Weapons (OPCW, Netherlands, Nobel peace prize winner of 2013), to control the CW threat worldwide. In the event of nerve agent poisoning, an anticholinergic drug, such as atropine sulfate, is used to antagonize the effects of excess acetylcholine at muscarinic receptor sites, and an oxime, such as pralidoxime chloride (2-PAM-Cl), is used to reactivate any unaged inhibited enzyme [2, 3]. However, this treatment regimen does not control the development of nerve agent-induced seizures [4, 5]. Concomitant administration of an anticonvulsant drug such as diazepam is considered essential to optimize the regimen of carbamate pretreatment plus atropine and oxime therapy for severely exposed casualties [6, 7]. Prolonged generalized seizures (status epilepticus) can begin rapidly after nerve agent exposure in humans [8–11]. Animal studies show these seizures can result in neuropathology and long-term behavioral deficits if not promptly controlled [12–16]. It is widely accepted that organophosphate (OP) induced seizure activities if not treated in a timely manner, can evolve into status epilepticus. This can cause an irreversible brain damage and long-term neurological, behavioral, and cognitive deficits [1, 17]. The neuropathological consequences of OP-poisoning are related to the severity and duration of seizure activity [16, 18].
Reactivation of inhibited acetylcholinesterase is considered to be an important element in post-exposure treatment. Bis-pyridinium oximes such as HI-6 can reactivate the phosphorylated enzyme if they are administered prior to the enzyme changes from the reactivatable to the unreactivatable state, the process referred to as “ageing” . Diazepam (DZ), the preferred anticonvulsant benzodiazepine (BZ) for the treatment of OP-nerve agent-induced seizures and neuronal damage has been associated with unwanted effects, poor bioavailability, anticonvulsant tolerance, and dependence liability. Diazepam was also found to be not always completely effective in protecting animals against soman-induced neuropathology [19, 20]. In a search for safer and more effective anticonvulsant BZs against OP-induced seizure and neuronal damage, Midazolam (MDZ), a non-selective and full positive allosteric modulator of GABA action at a variety of GABAA receptor subtypes , has recently been considered a possible anticonvulsant replacement for DZ . The advantages that have been attributed to MDZ include its rapid bioavailability and the ease of administration by intranasal, sublingual, and intramuscular routes . Gene expression studies during nerve agent exposure demonstrated several pathways in neurons including cholinergic, purinergic, NMDA-glutamatergic, GABAergic, catecholaminergic, serotogenic, calcium, and MAP kinase signaling along with genes related to ion channels, cytoskeletal proteins, cell adhesion, neurodegeneration, learning and memory, dementia/ataxia, mitochondrial dysfunction and apoptosis were altered significantly [23–26]. Excess muscarinic activation induced either by agonist application or by inhibition of AChE, results in long-lasting modifications of gene expression and protein levels of key cholinergic proteins [27, 28]. Several studies have successfully employed c-Fos activity as a marker of neural activity  and increased c-Fos expression has been linked with organophosphate administration [30, 31]. Convincing evidence suggest the role of free radicals in AChE inhibitors-induced neuronal cell and macromolecular damage [32, 33].
The relative lethality of nerve agents as determined in animal studies is VX > Soman > Sarin > Tabun . Among OP nerve agents, soman is considered as one of the most toxic due to its high lipophility and high affinity to the brain AChE and causes rapid ageing of AChE when compared to sarin, which is less lipophilic, however, its affinity to the brain AChE is also high [35, 36]. Soman poisoning is also most difficult to counteract due to soman induced epileptic seizures and related brain damage, may resist to current therapies, if not treated immediately [19, 20]. In view of this, soman represents most serious toxicant to test the therapeutic possibilities for nerve agents. Seizures might be one of the factors responsible for the late neurological effects of OP poisoning, it is important to determine the extent to which existing antidotes can reduce the seizures and diminish brain injury. Thus, there has been an active research effort to find out the molecular changes responsible for nerve agent-induced neurotoxicity to designing better drugs. A possible sequence of neurochemical events following nerve agent exposure is the inhibition of AChE causes an elevation of acetylcholine leading to massive activation of muscarinic and nicotinic receptors. Paralleled or sequenced activation of different pathways including phospholipases, protein kinases, proteases, transcription factors and generation of reactive oxygen and nitrogen species, may further account for the multiple neurotoxic effects resulting from nerve agent exposure. Thus, identifying the pathways and target genes will helps in the development of new pharmacological treatment to enhance recovery and repair processes in the nerve agent induced brain damage. In view of this, it is of interest to investigate the therapeutic effects of antidotes (HI-6, atropine and midazolam) on soman-induced neurodegeneration and the expression of c-Fos, Calpain, and Bax levels in the discrete rat brain areas.