Squalamine prevents motor and non-motor symptoms in the paraquat and lectin rat model of the body-first subtype of Parkinson's disease

Increasing evidence supports the existence of a distinct body-first subtype of Parkinson's disease (PD), in which the initial site of pathology is in the gut. Animal models that recapitulate the body-first subtype of PD are needed. We tested the hypothesis that non-motor features of the body-first subtype of PD are recapitulated in the paraquat and lectin (P + L) rat model of PD, a model that has previously demonstrated the pathological motor progression of this subtype of PD. Then, we tested whether oral squalamine, a gastrointestinal prokinetic that has been shown to reduce formation of pathological α-synuclein, could prevent pathology, motor, and non-motor findings. Rats (n = 93) were orally gavaged for seven days with paraquat (1 mg/kg) and lectin (0.05%) in 1% sucrose solution. A subset of rats (n = 37) were given 30 days of squalamine (20 mg/kg) in their drinking water immediately following P + L treatment. Rats were tested for parkinsonian motor deficits, gastrointestinal dysmotility, sleep abnormalities, and cognitive deficits. Rats were euthanized and their brains processed for phospho-S 129 -α-synuclein pathology and neurodegeneration. We show that the P + L rat model recapitulates non-motor features and pathology of gastrointestinal dysmotility and sleep abnormalities seen in the body-first subtype of PD. We show that oral squalamine prevents motor deficits, gastrointestinal dysmotility, and sleep abnormalities, and diminishes phospho-S 129 -α-synuclein pathology and neurodegeneration in the nigrostriatal pathway. We show that the P + L rat model recapitulates many features of the body-first subtype of PD and provides pre-clinical evidence for the use of squalamine to mitigate progression in the body-first subtype of PD.