Neurosteroid mitigation of developmental neurological dysfunction, long-term epileptic biomarkers, chronic neuroinflammation, and neurodegeneration in a pediatric rat model of organophosphate exposure.

Children are particularly susceptible to the neurotoxic effects of organophosphates, which can lead to developmental neuronal deficits and associated dysfunction, including cognitive disabilities, epilepsy, and associated comorbidities. Anticonvulsants like benzodiazepines fail to prevent the lasting neurobehavioral and neuropathological effects of organophosphate exposure, emphasizing the need for new anticonvulsants to address these effects. This study evaluated the efficacy of the synthetic neurosteroid ganaxolone (GX) in combating persistent behavioral deficits, electrographic abnormalities, and neuropathological damage induced by diisopropylfluorophosphate (DFP) intoxication in pediatric rats. Postnatal day 21 rats were exposed to DFP acutely and were treated with GX (5-10 mg/kg). Behavior deficits were systematically monitored up to 3 months after exposure. Video electroencephalography at 3 months assessed spontaneous recurrent seizures, nonconvulsive epileptiform discharges, high-frequency oscillations, and interictal spike activity. GX treatment significantly mitigated anxiety, aggression, memory deficits, and depression-like phenotypes in DFP-exposed pediatric animals. It also reduced DFP-induced occurrence of epileptic biomarkers such as spontaneous recurrent seizures, epileptiform discharges, interictal spikes, and high-frequency oscillations demonstrating potential disease-modifying effects. Histological analysis showed that GX decreased the loss of parvalbumin (+) inhibitory neurons, neuronal nuclei antigen (+) principal neurons, and aberrant mossy fiber sprouting. GX also reduced neuroinflammation, indicated by decreased ionized calcium binding adaptor molecule 1 (+) microgliosis. Together, these results demonstrate the neuroprotective activity of GX in mitigating chronic neurologic dysfunction, neuroinflammation, and neurodegeneration and confirm GX as a promising treatment option for DFP exposure. SIGNIFICANCE STATEMENT: Acute organophosphate (OP) intoxication poses a severe risk, particularly to children, leading to life-threatening seizures and long-term neurological deficits. Current treatments, including benzodiazepines, are less effective against persistent seizures and neurological sequel after acute exposure. This study explores the potential of ganaxolone, a synthetic neurosteroid, to mitigate the neurodevelopmental consequences of OP exposure. Our findings reveal that ganaxolone provides significant neuroprotection in a pediatric model of OP intoxication, reducing long-term seizures, ictal biomarkers, neurodegeneration, neuroinflammation, and associated neurological dysfunctions, offering a promising therapeutic avenue for pediatric victims of OP exposure.