Off-target effects of the NADPH oxidase inhibitor mitoapocynin-encapsulated nanoparticles and free-drug oral treatment in a rat DFP model of neurotoxicity

Abstract

Acute exposure to diisopropylfluorophosphate (DFP), an organophosphate (OP), produces chronic neurological effects such as spontaneous seizures and behavioural comorbidities. Achieving optimal drug bioavailability in the brain by conventional routes to treat OP-induced neurotoxicity is challenging. Therefore, we investigated polyanhydride nanoparticles (NPs)-mediated drug delivery via the intramuscular route in rats for improved bioavailability of an antioxidant, NADPH oxidase inhibitor mitoapocynin (MPO). We evaluated the tolerability of blank NPs (4 mg, i.m.), MPO-encapsulated NPs (MPO-NP, 4 mg, i.m., single dose) and free MPO-oral (60 mg/kg, daily for three days) after exposure to DFP. Bodyweight, serum biochemistry, and kidney, lung and liver histology revealed no adverse responses to blank NPs. Markers of oxidative stress, neuronal loss and astrocyte reactivity were also no different from control. In DFP-exposed animals treated with MPO-NP and MPO-oral, there was significant weight loss, abnormal liver and kidney parameters, and elevated GP91phox and astrocytes in the brain. Our findings demonstrate that NP delivery via the intramuscular route is safe. DFP and MPO induced off-target effects, but not DFP or MPO treatment alone, which highlights the complexity of dosing regimens in OP models. Intranasal MPO-NP delivery and dose optimisation in the DFP model are required to determine the efficacy of MPO in future studies.

Keywords: Polyanhydride nanoparticles; kidney function; liver function; mitoapocynin; off-target effects; organophosphate poisoning.