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. 2020 Jan 31;12:4.
doi: 10.3389/fnagi.2020.00004. eCollection 2020.

Strategies for the Treatment of Parkinson's Disease: Beyond Dopamine

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Free PMC article

Strategies for the Treatment of Parkinson's Disease: Beyond Dopamine

Alexandre Iarkov et al. Front Aging Neurosci. .
Free PMC article

Abstract

Parkinson's disease (PD) is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal α-synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.

Keywords: cotinine; gene therapy; precision medicine; prevention; stem cells.

Figures

Figure 1
Figure 1
Diagram depicting the dopaminergic system of the midbrain. The dotted lines indicate the dopaminergic regions of the midbrain. GP, globus pallidus; SNc, substantia nigra pars compacta; VTA, ventral tegmental area; RRF, retrorubral field; A8, A9, and A10—clusters of dopaminergic neurons in the midbrain (RRF, SNc, and VTA clusters, respectively).
Figure 2
Figure 2
Diagram describing the frontostriatal motor loop controlling motor function under physiological and parkinsonian states. The prefrontal cortex (PFC) participates in cognitive control and planning of movements. The premotor cortex organizes sequences of body actions, and the primary motor cortex is responsible for executing them. Excitatory signals, which are initiated by cortical glutamatergic neurons, project from the PFC to the premotor cortex, and then to the motor cortex through several subcortical structures. Then, the resultant signals received by the pyramidal cells of the motor cortex go to the motor neurons of the spinal cord. Together, this is called the frontostriatal motor loop. Midbrain dopaminergic neurons play an essential role in modulating the signals that go along the frontostriatal motor loop. Changes in the direct inhibitory (initiated by D2 receptors) and indirect (D1 receptors) pathways under parkinsonian states due to the loss of dopaminergic neurons in the SNc are indicated. GABA, γ-aminobutyric acid; SNc, substantia nigra pars compacta; GPe, globus pallidus external; GPi, globus pallidus internal; STN, subthalamic nucleus; PPN, peripeduncular nucleus.
Figure 3
Figure 3
Diagram depicting the striatal neurotransmitter systems modulating the responses of the striatal neurons to the premotor cortex and SN afferent signals. The direct and indirect pathways, as well as stimulating and inhibitory neurotransmitter receptors, are outlined. MSNs, medium spiny neurons; GABA, γ-aminobutyric acid; SNc, substantia nigra pars compacta; ACh, acetylcholine; Enk, enkephalin; Dyn, dynorphin; GABA (PLTS and FS), aspiny GABAergic interneurons, low-threshold spiking (PLTS) and fast-spiking (FS) neurons.

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