Chronic L-Dopa Therapy in Parkinson’s Disease: Can It Accelerate Degeneration of Nigrostriatal Dopaminergic Neurons?

Abstract

In Parkinson’s disease, there is a selective degeneration of the neuromelanin-containing dopaminergic neurons in the pars compacta with anterograde loss of the ascending nigrostriatal axonal projections and their terminal arborizations in the caudate and putamen nuclei. The cause of the progressive death of dopaminergic neurons is yet unknown. Among others, it may be due to an excessive intraneuronal production of cytotoxic free radicals. The dopaminergic neurons are particularly prone to free radical formation which occurs via two main processes, i.e., breakdown of dopamine by the enzyme monoamine oxidase and synthesis of the pigment neuromelanin. Under normal physiological circumstances, there is probably adequate protection of these neurons by the natural intracellular mechanisms that scavenge and neutralize the cytotoxic free radicals. Theoretically, in Parkinson’s disease there may be a basic failure of one or more of such defense mechanisms which leads to abnormal intraneuronal accumulation of cytotoxic free radicals and consequently to cell death. Another hypothetical possibility is that there is an overproduction of such harmful products, in excess of the neutralizing capacity of the protective apparatus, induced by exposure to MPTP-like neurotoxins derived from the₁external environment or through an endogenous metabolic derangement.