Drug therapy for Parkinson’s disease: An update

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting about 1% of the population above the age of 65. PD is characterized by a selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta. This results in a marked loss of striatal dopamine and the development of the characteristic features of the disease, i.e., bradykinesia, rest tremor, rigidity, gait abnormalities and postural instability. Other types of neurons/neurotransmitters are also involved in PD, including cholinergic, serotonergic, glutamatergic, adenosine, and GABAergic neurotransmission which might have relevance to the motor, non-motor, neuropsychiatric and cognitive disturbances that occur in the course of the disease. The treatment of PD relies on replacement therapy with levodopa (L-dopa), the precursor of dopamine, in combination with a peripheral decarboxylase inhibitor (carbidopa or benserazide). The effect of L-dopa, however, declines over time together with the development of motor complications especially dyskinesia in a significant proportion of patients within 5 years of therapy. Other drugs include dopamine-receptor-agonists, catechol-O-methyltransferase inhibitors, monoamine oxidase type B (MAO-B) inhibitors, anticholinergics and adjuvant therapy with the antiviral drug and the N-methyl-D-aspartate glutamate receptor antagonist amantadine. Although, these medications can result in substantial improvements in parkinsonian symptoms, especially during the early stages of the disease, they are often not successful in advanced disease. Moreover, dopaminergic cell death continues over time, emphasizing the need for neuroprotective or neuroregenerative therapies. In recent years, research has focused on non-dopaminergic approach such as the use of A_2A receptor antagonists: istradefylline and preladenant or the calcium channel antagonist isradipine. Safinamide is a selective and reversible inhibitor of MAO-B, a glutamate receptor inhibitor as well as sodium and calcium channel blocker. Minocycline and pioglitazone are other agents which have been shown to prevent dopaminergic nigral cell loss in animal models of PD. There is also an evidence to suggest a benefit from iron chelation therapy with deferiprone and from the use of antioxidants or mitochondrial function enhancers such as creatine, alpha-lipoic acid, l-carnitine, and coenzyme Q10.

Keywords: Parkinson disease; Levodopa; Dopaminergic drugs; Neuroprotective agents; Non-dopaminergic drugs; Mitochondrial enhancers

Core tip: Parkinson’s disease (PD) is a neurodegenerative disorder for which currently there is no cure. The advent of many therapies such as levodopa (L-dopa), dopamine-receptor-agonists, monoamine oxidase type B inhibitors, and catechol-O-methyltransferase inhibitors helped much to ease the life and to improve health-related quality of life of PD patients. Among these drugs, L-dopa remains the most effective agent for treatment of motor symptoms in PD. These agents provide symptomatic relief for motor symptoms but there is no evidence that these could alter the natural course of the disease and prevent the progressive dopaminergic neuronal loss. There is, however, encouraging data that suggest a benefit from iron chelation therapy with deferiprone and from the use of antioxidants or mitochondrial function enhancers in preventing or delaying the progression of PD.