The ionizing zwitterionic oxime antidote attenuates gliosis in mice exposed to sarin

Toxic organophosphates like the nerve agent sarin readily cross the blood-brain barrier (BBB) and inhibit acetylcholinesterase (AChE), a pivotal enzyme in regulating neurotransmission by hydrolysis of acetylcholine (ACh). Elevated levels and prolonged residence time of ACh initiate seizures and activation of glial cells leading to neuroinflammation. Furthermore, AChE inhibition induces life-threatening symptoms if not treated promptly with atropine and an oxime reactivator of inhibited AChE. The oximes approved for therapy (e.g. 2-PAM) poorly cross the BBB due to their permanent positive charge and do not restore synaptic AChE activity, leaving the brain vulnerable to long-term damage. In this study, we investigated whether treatment with the centrally-active oxime RS194B acts protectively on the brain of mice exposed to sarin. We compared the levels of specific proteins expressed in neuronal and glial cells of mice treated with RS194B after sarin exposure with those of sarin-exposed mice, mice treated with 2-PAM, and untreated control mice. The level of Iba-1 protein was investigated as a measure of microgliosis, and GFAP of astrogliosis, whereas neuronal cell viability was assessed by detecting NeuN immunoreactivity. Our results indicated that sarin-induced gliosis was suppressed in mice treated with RS194B, in contrast to mice treated with 2-PAM. Treatment with RS194B re-established the physiological function of AChE, thus correcting the neurochemical imbalance of ACh that initiates seizures and leads to neuroinflammation. Overall, our results highlight the significance of restoring synaptic AChE activity extending beyond merely mitigating cholinergic crisis.