Effect of PACAP on the progression of Parkinson's disease in chronic mouse model

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Parkinson's disease (PD) is a progressive incurable neurological disease that affects 1-2 million people in the U.S. The cardinal motor symptoms of PD are believed to be due to the degeneration of dopaminergic neurons in the pars compacta of the substantia nigra. However, patients with PD suffer from a number of symptoms such as hyposmia, sleep disturbances, depression, hypotonia, and constipation that cannot be due only to the degeneration of nigral dopaminergic neurons. Intracytoplasmic (Lewy bodies) and intraneuritic (Lewy neurites) inclusions that contain alpha-synuclein are the pathological hallmarks of PD. alpha-Synuclein plays a critical role in the etiology of PD. In addition to the brain, Lewy body and neurite pathologies appear in the peripheral autonomic nervous system early in the disease process. The systemic degenerations that occur in PD start in peripheral neuronal systems and progress centripetally and then caudal to rostral within the CNS. Our hypothesis is that pituitary adenylate cyclase-activating polypeptide (PACAP) administered after the onset of motor dysfunction will halt or slow the progression of PD. PACAP is a pleiotropic peptide with both potent anti-inflammatory and potent cytoprotective properties. PACAP significantly reduces the degeneration of nigral dopaminergic neurons caused by either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6- hydroxydopamine. However, both of these neurotoxins cause PD-like symptoms in hours while PD usually takes decades for symptoms to develop. It is exceedingly unlikely that the nervous system responds in the same way to extremely rapid and slowly progressive diseases. The predictive value of these acute models for a progressive chronic disease is questionable. Therefore, there is a huge unmet need for an animal model that better mimics the human conditions. The alpha-synuclein over-expressing transgenic (A53T) mice seem to meet these expectations. The first autonomic dysfunctions in the urinary and intestinal tracts appear at 4 month of age in these mice while the motor dysfunction appears at 10-11 months of age. The slow progression and the organ-selective appearance of the symptoms in the A53T mice are similar to those in humans with PD. Although PACAP has remarkable cytoprotective and anti-inflammatory properties, its half-life in the bloodstream is short and, therefore, its use for chronic diseases is not practical. Therefore, we will evaluate our proprietary, metabolically stable PACAP analogs for neuroprotection in the A53T mouse model of PD. Specific Aim 1: Provide evidence that PACAP administered after the onset of motor dysfunction will halt or slow the progression of PD-like symptoms. Specific Aim 2: Provide evidence that the metabolically stable and receptor subtype-specific PACAP analogs administered as described in Specific Aim 1 will also halt or slow the progression of PD-like symptoms. Motor dysfunction (cylinder test, paw-print analysis, and grip strength) will be tested biweekly before and during treatment, and then the brains of the mice will be processed for PD pathology (alpha-synuclein, Lewy bodies, tyrosine hydroxylase, and apoptotic and inflammatory markers).