L-DOPA, or levodopa, is an amino acid precursor of dopamine, a neurotransmitter essential for the functioning of the central nervous system. It is mainly used as a treatment for Parkinson’s disease, a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra, a region of the midbrain. Taking L-DOPA allows a person to increase dopamine levels in the brain, temporarily compensating for the dopaminergic deficit caused by the disease. From a biological point of view, L-DOPA crosses the blood-brain barrier via the aromatic amino acid transporter and, once inside the central nervous system, is converted into dopamine by the enzyme aromatic amino acid decarboxylase (AADC). However, the therapeutic efficacy of L-DOPA is limited by the fact that a significant portion of the molecule is metabolized into dopamine in peripheral tissues before reaching the brain.
To overcome this problem, L-DOPA is administered in combination with inhibitors of peripheral decarboxylase, such as carbidopa or benserazide, which increase its bioavailability in the brain. At the cellular level, the dopamine produced by L-DOPA interacts with dopamine receptors on nerve cells, activating a series of intracellular signaling pathways that influence neuronal activity, synaptic plasticity, and the release of other neurotransmitters. However, chronic use of L-DOPA can cause motor complications, such as L-DOPA-induced dyskinesias, phenomena characterized by abnormal involuntary movements. These side effects are related to maladaptive changes in dopamine circuitry, including aberrant regulation of dopamine D1 and D2 receptors, changes in glutamatergic transmission, and alterations in intracellular signaling, such as that mediated by protein kinase A (PKA) and phosphorylation of the DARPP-32 protein.
But this does not appear to be the full picture. For a long time, levodopa was considered the inert version of dopamine awaiting metabolic conversion to become pharmacologically active. Instead, a few years ago researchers discovered that L-DOPA is a ligand for the GPR143 receptor, a receptor previously considered an orphan and associated with ocular albinism. The researchers found that L-DOPA and its receptor GPR143 regulate neurogenesis in the dentate gyrus in a dopamine-independent manner. L-DOPA at concentrations much lower than dopamine promoted neural stem and progenitor cell proliferation in wild-type mice upon inhibition of its conversion to dopamine; this effect was abolished in GPR143-deficient (Gpr143-/y) mice. Hippocampal neurogenesis was decreased during development and adulthood, and exacerbated depression-like behavior was observed in adult Gpr143-/y mice.
This information, on the one hand, lends strength to the old monoaminergic theory underlying depression, which suggested the lack of biogenic amines (dopamine, noradrenaline, especially), as the cause of the onset of the condition. Also because there are experimental data that indicate how the GPR143 receptor couples physically and functionally with the dopamine D2 receptor and the alpha-1b adrenergic receptor, especially at the level of brain astrocytes. In these cells, the activation of the receptor with L-DOPA induces their proliferation, but scientists do not yet know the implications of this phenomenon on brain biology. Furthermore, recent studies suggest that L-DOPA could have neurotoxic effects in some conditions, promoting oxidative stress and the production of free radicals (ROS) through dopamine metabolism. This phenomenon is particularly relevant in patients with reduced antioxidant reserves or with high dopaminergic metabolic activity.
In addition, synthetic GPR143 antagonists have been identified, one of which is pimozide, a drug used in maintenance antipsychotic therapy for patients with schizophrenia and tics resistant to conventional drug therapy. But despite these potential adverse effects, L-DOPA remains the most effective treatment for the control of motor symptoms of Parkinson’s, with a generally favorable risk-benefit balance in the early stages of the disease.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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