Authors :
Presenting Author: Tanveer SINGH, PhD – Texas A & M university
Sreevidhya Ramakrishnan, PhD – Postdoctoral Research Associate, Neuroscience and experimental therapeutics, Texas A & m university; Xin Wu, MD – Assistant Professor, Neuroscience and experimental therapeutics, Texas A & m university; D. Samba Reddy, PhD – Professor, Neuroscience and experimental therapeutics, Texas A & m university
Rationale:
Refractory status epilepticus (RSE) is typified by persistent seizures that sustain despite treatment with a benzodiazepine and antiseizure medications (ASM). RSE develops in up to 40% of SE patients and causes death in 35% of adults. In RSE, inadequate seizure control leads to irreversible neuronal damage and long-term neurological effects in children and adults. Organophosphates (OP) are neurotoxic chemicals that can induce seizures and RSE. The current anticonvulsants (midazolam) are less effective for OP exposure and RSE. Novel neuroprotectants are needed for delayed treatment to prevent the long-term effects. Neurosteroids, which are positive modulators of extrasynaptic GABA-A receptors, are currently considered as a new class of anticonvulsants and neuroprotectants. In this study, we investigated the long-term efficacy of two novel neurosteroid (NS) analogs in a rat OP model of RSE following delayed therapy (≥40 min).
Methods:
Adult rats were exposed to diisopropylfluorophosphate (DFP) to induce RSE and treated with midazolam. Novel NS analogs were administered in combination with midazolam. Animals were assessed for an array of behaviors and neuropathology at three months post exposure.
Results:
DFP-exposed post-SE rats exhibited significant neurological effects, such as aggressive behavior, heightened anxiety, object recognition memory deficits, and depression. They also exhibited impaired spatial learning and memory. Adjunct therapy with NS analogs significantly prevented behavioral dysfunction, cognitive deficits, and neuronal damage
Conclusions:
The results show that novel NS analogs can prevent long-term neurological effects caused by acute OP intoxication induced RSE.
Funding:
This work was supported by NIH Grant #U01-NS117278* (to D.S.R.).