Abstract
Background:There are currently no therapeutic options for patients with Parkinson's disease that prevent or slow the death of dopaminergic neurons. We have recently identified the novel P7C3 class of neuroprotective molecules that blocks neuron cell death.AIMS:The aim of this study was to determine whether treatment with highly active members of the P7C3 series blocks dopaminergic neuron cell death and associated behavioral and neurochemical deficits in the rat 6-hydroxydopamine (6-OHDA) model of Parkinson's disease.Methods:After unilateral injection of 6-OHDA into the median forebrain bundle, rats were assessed for behavioral function in the open field, cylinder test, and amphetamine-induced circling test. Thereafter, their brains were subjected to neurochemical and immunohistochemical analysis of dopaminergic neuron survival. Analysis was conducted as a function of treatment with P7C3 compounds, with administration initiated either before or after 6-OHDA exposure.Results:Animals administered P7C3-A20 or P7C3-S243, two of the most advanced agents in the P7C3 series of neuroprotective compounds, both before and after 6-OHDA exposure showed evidence of protective efficacy in all measures. When P7C3-S243 administration was initiated after 6-OHDA exposure, rats also showed protective efficacy in all measures, which included blocking dopaminergic neuron cell death in ipsilateral substantia nigra pars compacta, preservation of dopamine and its metabolites in ipsilateral striatum, and preservation of normal motor behavior.Conclusions:The P7C3 series of compounds may form the basis for developing new therapeutic agents for slowing or preventing progression of Parkinson's disease.
Highlights
Parkinson’s disease (PD) is a progressive and currently incurable neurodegenerative disease characterized by death of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNc)
We chose to inject the toxin into the median forebrain bundle (MFB) because this approach induces degeneration in striatal terminals before dopaminergic neuron cell death occurs,[17] and we have previously shown that P7C3 compounds block axonal degeneration preceding neuron cell death in traumatic brain injury.[11]
Rats were evaluated for motor ability via three behavioral tests: assessment of rearing ability in the cylinder test, assessment of distance traveled in the open field test, and amphetamine-induced circling
Summary
Parkinson’s disease (PD) is a progressive and currently incurable neurodegenerative disease characterized by death of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNc). AIMS: The aim of this study was to determine whether treatment with highly active members of the P7C3 series blocks dopaminergic neuron cell death and associated behavioral and neurochemical deficits in the rat 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease. METHODS: After unilateral injection of 6-OHDA into the median forebrain bundle, rats were assessed for behavioral function in the open field, cylinder test, and amphetamine-induced circling test. Thereafter, their brains were subjected to neurochemical and immunohistochemical analysis of dopaminergic neuron survival. When P7C3-S243 administration was initiated after 6-OHDA exposure, rats showed protective efficacy in all measures, which included blocking dopaminergic neuron cell death in ipsilateral substantia nigra pars compacta, preservation of dopamine and its metabolites in ipsilateral striatum, and preservation of normal motor behavior. CONCLUSIONS: The P7C3 series of compounds may form the basis for developing new therapeutic agents for slowing or preventing progression of Parkinson’s disease
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