Objective/Rationale:
Dehydroepiandrosterone (DHEA), a common neutraceutical and potent neuro-steroid has been suggested as a neuroprotective treatment for Parkinson’s disease (PD). However, DHEA is very poorly absorbed when given orally, is rapidly disposed of by the body and metabolized into sex steroids. HE3286 is a synthetic steroid based on an active metabolite of DHEA that may possess potent neuroprotective effects. HE3286 is orally active, metabolically stabilized and has demonstrated safety and activity in clinical trials.
Project Description:
Making use of a chemical (MPTP) that causes brain inflammation, destroys neurons and induces Parkinson-like symptoms in mice and pre-clinical models (and humans), we will test the ability of HE3286 to enter brain tissue, reduce inflammation and protect the same neurons that are progressively lost in PD. A pre-clinical model will be treated with HE3286 or with placebo after exposure to MPTP and PD symptoms, neuro-inflammation and neuronal loss assessed. If HE3286 is determined to be effective in this pre-clinical model, similar studies will be conducted in a more relevant model of PD established by our collaborators. Success in both models would enable rapid entry of HE3286 into clinical trials in patients with PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
An inflammatory response in brain tissue may activate and exacerbate the neuro-degenerative process in PD, forming a vicious cycle that leads to cell death and disease progression. In brain, DHEA acts to balance the inflammatory process and protect neurons from its damaging consequences. As a pharmaceutically improved synthetic derivative of a potent anti-inflammatory DHEA metabolite, HE3286 may interrupt the inflammatory cycle, restore homeostasis, protect neurons and delay or prevent the progression of disease.
Anticipated Outcome:
We expect to confirm our hypothesis that HE3286 can enter brain tissue, reduce inflammation and improve symptoms of PD in pre-clinical models. HE3286 has been studied in approximately 170 patients and healthy volunteers. It’s anti-inflammatory activity has been demonstrated in humans by the ability to down regulate pro-inflammatory signals that have specific relevance to PD. HE3286 is very well tolerated when administered chronically, and, if successful in our PD pre-clinical studies, could proceed quickly into clinical trials in patients with PD.
Final Outcome
We have demonstrated that oral HE3286, a safe, synthetic derivative of an anti-inflammatory neurosteroid currently in phase II development as treatment for inflammatory disease, efficiently penetrates the pre-clinical blood-brain barrier. We conclude that HE3286, when given orally, can achieve and sustain pharmacologically relevant concentrations in the brain. Further, we found that treatment of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) intoxicated pre-clinical models (the preferred agent to induce parkinsonism in laboratory pre-clinical models) with HE3286 was associated with significant improvement in motor function. Improved motor function was associated with reduced neuro-inflammation as determined by reduced gene expression of key inflammatory mediators in the brain (iNOS, TNF??and IL-1?)?? Neuronal architecture was highly preserved by the treatment with this compound as observed by histology. We observed no synergy or additive effects when HE3286 was given with levodopa. While certain confirmatory studies remain in progress, our data to date suggest a potential role for HE3286 in the treatment of PD and parkinsonism-related disorders and provide incentive for further investigation.