Studies On The Correlation Between Metabotropic Glutamate Receptors And Parkinson Disease

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, afflicting almost approximately 1.4% of the population over the age of 55, the mean age at which the disease is first diagnosed. Prevalence and incidence will both increase steadily with the ageing population of the world. It has formed an increasing economic burden for society and also become an ever more urgent international healthcare concern.PD is named after the physician James Parkinson, who published a formal description of the disorder in 1817 entitled " An Essay on the Shaking Palsy." For this reason, Parkinson's disease is sometimes also referred to as shaking palsy or paralysis agitans. This disease is characterized clinically by bradykinesia (slowness of movement), muscular rigidity, tremor at rest, and postural abnormalities. These clinical symptoms result from the highly selective degeneration of a small group of neuromelanin-containing dopaminergic neurons in the midbrain. Many surviving neurons contain large, cytoplasmic, proteinaceous inclusions known as Lewy bodies, which are the pathological hallmark of PD. However, these symptoms do not appear until there is approximately a 70-80% reduction in the dopamine levels in the striatum. Surprisingly, no simple and reliable early-detection tests exist to predict persons at risk for PD long before they ever show overt signs of this disease. Although the symptoms and neuropathology of PD have been well characterized, the underlying mechanisms and causes of the disease remain largely enigmatic.In PD, the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) triggers a cascade of functional changes affecting thewhole basal ganglia (BG) network. The most relevant alterations affect the output nuclei of the circuit, the medial globus pallidus and substantia nigra pars reticulata (SNr), which become hyperactive. Such hyperactivity is sustained by the enhanced glutamatergic inputs that the output nuclei receive from the subthalamic nucleus. The overactivity of the glutamatergic STN projection to the BG output nuclei results in an inhibition of thalamocortical neurons. An imbalance of activity between the direct and indirect striatofugal pathways in favor of the indirect pathway is thought to underlie most symptoms of PD. Recently developed surgical therapies that are aimed at reducing activity through the indirect pathway, have been distinctly effective. Unfortunately, these approaches are highly invasive, extremely expensive, and assessable to a small minority of patients. Long-term effects are unknown, and surgical therapies only reserved for patients that can no longer be helped by dopamine replacement therapy. Thus new effort has been dedicated to finding pharmacological treatment options that will be effective in reducing transmission through the indirect pathway. The current pharmacotherapies are aimed at replacing the missing dopamine. DA precursor L-Dopa and/or DA agonists, has been the mainstay of pharmacotherapy for this disease. However, treatment with these dopaminomimetics does not mitigate progression of the process underlying PD, a factor that is thought to be causatively involved in the declining efficacy and occurrence of motor complications upon continued pharmacotherapy with such compounds. To optimally manage PD, there is still a strong requirement for drugs capable of retarding or, ideally, halting the ongoing degeneration of dopaminergic neurons in the substantia nigra. This realization has led to intensive investigation of the neuroprotective potential of various agents.Glutamate and y -amino butyric acid (GABA), respectively, are the major excitatory and inhibitory neurotransmitters in the CNS, provide the outcoming and incoming fast signals through the BG. The BG are a group of interconnected subcortical nuclei that, together with the thalamus and motor cortex, comprise the motor circuit responsible for the fine coordination of voluntary motor function. In PD, degeneration of the nigrostriatal pathway and subseque...