Mitigating Organophosphate Nerve Agent, Soman (GD)-Induced Long-Term Neurotoxicity: Saracatinib, a Src Tyrosine...

Acute exposure to soman (GD), an organophosphate nerve agent (OPNA), irreversibly inhibits acetylcholinesterase (AChE), induces seizures, and could be fatal if not treated immediately. Existing medical countermeasures (MCMs- atropine, oximes, and benzodiazepines) mitigate the acute life-threatening cholinergic symptoms but have limited protection against long-term neurological damage in survivors. This indicates a need for an effective adjunct therapy to mitigate cognitive, behavioral, and brain pathology associated with OPNA exposure. Saracatinib (SAR), a selective Src tyrosine kinase inhibitor, has emerged as a potential candidate, given its protective properties in experimental models of excitotoxicity and neuroinflammation. Here, we evaluate the therapeutic efficacy of SAR in mitigating long-term neurological deficits triggered by acute exposure to soman in a rat model.

Mixed-sex adult Sprague Dawley rats were exposed to soman (132 μg/kg, s.c.) and immediately treated with atropine (2 mg/kg, i.m.) and HI-6 (125 mg/kg, i.m.). Seizure severity was quantified for an hour before administering midazolam (3 mg/kg, i.m.). One-hour post-midazolam, SAR/vehicle was administered orally and daily for 18 weeks in the diet. After behavioral testing, brain MRI, and EEG acquisition, animals were perfused with 4% paraformaldehyde at 18 weeks post-soman. Serum and CSF were collected for nitro-oxidative markers and proinflammatory cytokines. Brains were processed for neuroinflammation and neurodegeneration markers.

SAR treatment attenuated the soman-induced anxiety/fear-like behavior and motor impairment and modulated the severity, frequency, and duration of seizures. Despite improved hippocampal functional connectivity (MRI), SAR did not reverse soman-induced learning and memory deficits at 5-7 weeks. However, 18 weeks of SAR treatment demonstrated anti-inflammatory and antioxidant properties, mitigated reactive gliosis and neurodegeneration, and partially protected somatostatin parvalbumin inhibitory neurons. The glial scars in the amygdala were reduced in SAR-treated animals compared to the vehicle-treated group.

Long-term SAR treatment revealed disease-modifying effects by protecting the brain from soman-induced neuroinflammation and neurodegeneration, while also reducing seizure severity and modulating the frequency and duration of seizures. Furthermore, it provided partial protection against behavioral impairments and MRI deficits in the short term. These findings highlight the therapeutic potential of Src tyrosine kinase inhibition in addressing chronic neurotoxicity induced by soman.