Abstract Details

Despite the many risks of smoking tobacco, the risk of PD is markedly reduced among smokers and may derive from biological activity of specific tobacco smoke constituent(s). On the basis of accumulating evidence supporting the therapeutic potential of CO in other disease contexts, this study set out to determine whether low dose CO is neuroprotective in PD models.

To evaluate the neuroprotective potential of low dose CO treatment in Parkinson disease (PD) models.

In an AAV-alpha-synuclein (aSyn) model, rats underwent right nigral injection of AAV1/2- asynA53T and left injection of empty AAV, followed by treatment with oral CO drug product (HBI-002 10ml/kg, daily by gavage) or vehicle. In a short-term MPTP model (40mg/kg, i.p.), mice were treated with inhaled CO (iCO) (250ppm) or air. In an in vitro rotenone model, SH-SY5Y cells exposed to rotenone were treated with CO (200 ppm) or air. All analyses, including immunohistochemistry for nigral aSyn and tyrosine hydroxylase, HPLC measurement of striatal dopamine, stereological cell counting, and biochemical analyses were conducted blinded to treatment condition.

Each HBI-002 treatment increased carboxy-hemoglobin to 6%. In the aSyn model, treatment with HBI-002 reduced ipsilateral loss of both striatal dopamine and TH-positive neurons in the substantia nigra pars compacta, and HBI-002 reduced aSyn aggregates and aSyn S129 phosphorylation. In the MPTP model, treatment with low dose iCO also reduced loss of striatal dopamine and loss of TH+ neurons. In saline-treated mice, iCO had no effect on striatal dopamine or TH+ cell counts. HBI-002 upregulated heme oxygenase-1, HIF-1a, and cathepsin D. In the rotenone model, treatment with low dose CO reduced cell death.