engleski

CNS-active reactivator of inhibited acetylcholinesterase provides neuroprotection in mice exposed to nerve agent

Acutely toxic organophosphates (OP) readily cross the blood-brain barrier (BBB) and inhibit the enzyme acetylcholinesterase (AChE). Consequently, increased level and residence time of neurotransmitter acetylcholine leads to seizures and activation of glial cells. If not treated by reactivators of AChE activity and an antimuscarinic drug, OP poisoning causes hypoxia, vasodepression, and respiratory arrest, followed by death. Nevertheless, reactivators currently in use are quaternary compounds that do not cross the BBB and cannot restore the activity of synaptic AChE, leaving the brain vulnerable to long-term damage. We anticipate that the treatment with uncharged, but ionizable oximes that cross the BBB and reactivate OP-inhibited synaptic AChE will act protectively on the brain of mice exposed to a nerve agent. For that purpose, we have investigated the effect of centrally acting RS194B oxime in the brain of mice exposed to a nerve agent by comparing detected levels of specific proteins expressed in neuronal and glial cells in the brains of OP exposed mice with mice treated by oxime therapy and untreated control mice. An increased level of IBA-1 protein detected a microglial response, and astrogliosis due to the accumulation of GFAP protein was also evident in poisoned mice. Nevertheless, our results indicated that therapy with RS194B acted neuroprotective when compared to OP exposed mice, and mice treated with standard oxime 2-PAM, especially up to 1.5 h after OP exposure. Moreover, in that period we observed that neuronal cell viability detected with NeuN immunoreactivity, was in the control range in mice treated with RS194B, unlike in OP exposed, and 2-PAM treated mice where NeuN levels were significantly below control. In conclusion, we can indicate the survival of neurons and neuroprotection by RS194B therapy but further immunohistochemical studies are planned for confirmation. Acknowledgement: This research was supported by the HDTRA-19-1-006-UCSD-113020, HrZZ- IP-2018-01-7683, and HrZZ-IP-2016-06-8636.

organophosphate ; oxime ; neuroinflammation ; neuroprotection ; NeuN ; IBA-1

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