Low Dose Carbon Monoxide Is Neuroprotective in Models of Parkinson’s Disease (S42.008)

Abstract

<h3>Objective:</h3> To evaluate the neuroprotective potential of low dose CO treatment in Parkinson disease (PD) models. <h3>Background:</h3> 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. <h3>Design/Methods:</h3> 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. <h3>Results:</h3> 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. <h3>Conclusions:</h3> These results demonstrating reduced cell death and aSyn pathology in animal and cell models support the therapeutic potential of low dose CO for PD. <b>Disclosure:</b> Dr. Gomperts has received personal compensation in the range of $0-$499 for serving as a Consultant for EIP. Dr. Gomperts has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Jannsen. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from LBDA. The institution of Dr. Gomperts has received research support from DOD/CDMRP. The institution of Dr. Gomperts has received research support from FFFPRI. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from MJFF. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from MJFF. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from NIH. Dr. Rose has nothing to disclose. Dr. Zorlu has nothing to disclose. Dr. Xue has nothing to disclose. Dr. Cai has received personal compensation for serving as an employee of Pfizer . Ms. Lin has nothing to disclose. Mr. Lee has nothing to disclose. Dr. Gomperts has stock in Hillhurst Biopharmaceuticals inc. The institution of Dr. Gomperts has received research support from Hillhurst Biopharmaceuticals inc. Dr. Gomperts has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bial Biotech (indirectly, as a service of the Parkinson Study Group service). The institution of Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen (indirectly, as a service of the Parkinson Study Group service). The institution of Dr. Schwarzschild has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB (indirectly, as a service of the Parkinson Study Group service). Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly. The institution of Dr. Schwarzschild has received research support from NIH. The institution of Dr. Schwarzschild has received research support from Parkinson’s Foundation. The institution of Dr. Schwarzschild has received research support from Michael J Fox Foundation. The institution of Dr. Schwarzschild has received research support from Farmer Family Foundation. Dr. Schwarzschild has a non-compensated relationship as a Chair, Executive Committee with the Parkinson Study Group that is relevant to AAN interests or activities. Dr. Chen has nothing to disclose.