Long-term Seizures, Neuropathology and Behavioral Response of Adult Rats After OP Status Epilepticus: Effect of Novel Neuroprotectants
Abstract number :
1.279
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2022
Submission ID :
2204602
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:25 AM
Authors :
Sreevidhya Ramakrishnan, PhD – Texas A&M University College of Medicine; Tanveer Singh, PhD – Postdoctoral Research Associate, Neuroscience and Experimental Therapeutics, Texas A&M University College of Medicine; Xin Wu, PhD – Research Assistant Professor, Neuroscience and Experimental Therapeutics, Texas A&M University College of Medicine; D. Samba Reddy, PhD, RPh, FAAAS, FAAPS, FAES – Professor, Neuroscience and Experimental Therapeutics, Texas A&M University College of Medicine
Rationale: Nerve agents and organophosphates (OP), such as diisopropylfluorophosphate (DFP), are lethal chemicals that can induce acute seizures, status epilepticus (SE), and mortality. The current antidotes work if given within 30 minutes of OP exposure. This timeline is often not practical for first responders to arrive and assist after a chemical attack. Thus, there is an urgent need for new anticonvulsants for OP-induced SE, especially for delayed treatment. Neurosteroids, which are positive modulators of GABA-A receptors, are currently considered a new class of anticonvulsants. In this study, we investigated the long-term efficacy of novel neurosteroid (NS) analogs in rats exposed to DFP following delayed therapy (≥ 40 min).
Methods: Adult rats were exposed to DFP and treated with standard antidotes to mitigate the acute neurotoxicity. Novel NS analogs were administered at 40-min post DFP exposure in combination with midazolam. Animals were assessed for seizures and behavior at the monthly interval, and neuropathology was examined at three months.
Results: DFP-exposed rats exhibited robust seizures, discharges, and high-frequency oscillations (HFOs). Additionally, they displayed aggressive behavior, heightened anxiety, object recognition memory deficits, and poor social interactions. They exhibited impaired spatial learning and memory. Delayed therapy with NS analogs significantly attenuated long-term seizures, behavioral and cognitive deficits, and electrographic abnormalities.
Conclusions: These results show that novel NS analogs can prevent long-term seizure susceptibility and co-morbid behavior deficits caused by prolonged SE.
Funding: This work was supported by NIH Grant #U01-NS117278* (to D.S.R.).
Anti-seizure Medications