The promise of neuroprotective agents in Parkinson's disease

Abstract

Parkinson's disease (PD) is characterized by loss of dopamine neurons in the substantia nigra of the brain. Since there are limited treatment options for PD, neuroprotective agents are currently being tested as a means to slow disease progression. Agents targeting oxidative stress, mitochondrial dysfunction, and inflammation are prime candidates for neuroprotection. This review identifies Rasagiline, Minocycline, and creatine, as the most promising neuroprotective agents for PD, and they are all currently in phase III trials. Other agents possessing protective characteristics in delaying PD include stimulants, vitamins, supplements, and other drugs. Additionally, combination therapies also show benefits in slowing PD progression. The identification of neuroprotective agents for PD provides us with therapeutic opportunities for modifying the course of disease progression and, perhaps, reducing the risk of onset when preclinical biomarkers become available.

Keywords: Parkinson’s disease; neurodegeneration; neuroprotection.

Figure 1

The mechanisms of action of neuroprotective agents that are in clinical trials. Rasagiline shows neuroprotective properties by suppressing mitochondrial apoptosis stopping the mitochondrial permeability transition pore (MPT) opening by inhibiting caspase-3, nuclear poly [ADP-ribose] polymerase 1 (PARP-1) activation, stopping the translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and halting nucleosomal DNA fragmentation. Rasagiline increases the expression of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL) through the protein kinase C (PKC) pathway, in addition to down-regulating the pro-apoptotic Bcl-2-associated death promoter (Bad) and Bcl-2-associated X protein (Bax). Minocycline inhibits the inflammatory response to prevent cell death and it chealates metals. Creatine inhibits activation of the MPT and represses iron (Fe²⁺) accumulation.