Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interactions between apparently separate dopaminergic and glutamatergic pathways figure prominently in the pathophysiology of Parkinson's Disease. So it is surprising that the ventral midbrain dopamine neurons, which give rise to the dopaminergic pathway, may themselves also be glutamatergic. We have addressed this idea in both rat and monkey brain and found that most ventral midbrain dopamine neurons exhibit glutamate immunoreactivity. We used postnatal cell culture to examine ventral midbrain dopamine neurons more closely. In vitro most dopamine neurons exhibit glutamate immunoreactivity, as well as immunoreactivity for phosphate-activated glutaminase, the enzyme principally responsible for the synthesis of neurotransmitter glutamate; inhibition of glutaminase reduces glutamate staining. In single cell microcultures, dopamine neurons make both dopaminergic and glutamatergic synaptic varicosities. Stimulation of individual dopamine neurons evokes a fast excitatory synaptic response mediated by glutamate; it also evokes dopamine release that inhibits the excitatory response via presynaptic D2 receptors. Thus, dopamine neurons appear to exert rapid synaptic actions via their glutamatergic synapses and slower modulatory actions via their dopaminergic synapses, including possibly inhibition of their own glutamatergic synapses. So, in the setting of dopamine neuron demise, there will be a loss of both dopaminergic and glutamatergic inputs to the striatum; furthermore, glutamate released by dopamine neurons may contribute to an excitotoxic cascade and the death of neighboring dopamine neurons.
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PMID:Glutamate is a cotransmitter in ventral midbrain dopamine neurons. 1133 Nov 97

Glutamate released by activated microglia induces excitoneurotoxicity and may contribute to neuronal damage in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition, tumor necrosis factor-alpha (TNF-alpha) secreted from activated microglia may elicit neurodegeneration through caspase-dependent cascades and silencing cell survival signals. However, direct neurotoxicity of TNF-alpha is relatively weak, because TNF-alpha also increases production of neuroprotective factors. Accordingly, it is still controversial how TNF-alpha exerts neurotoxicity in neurodegenerative diseases. Here we have shown that TNF-alpha is the key cytokine that stimulates extensive microglial glutamate release in an autocrine manner by up-regulating glutaminase to cause excitoneurotoxicity. Further, we have demonstrated that the connexin 32 hemichannel of the gap junction is another main source of glutamate release from microglia besides glutamate transporters. Although pharmacological blockade of glutamate receptors is a promising therapeutic candidate for neurodegenerative diseases, the associated perturbation of physiological glutamate signals has severe adverse side effects. The unique mechanism of microglial glutamate release that we describe here is another potential therapeutic target. We rescued neuronal cell death in vitro by using a glutaminase inhibitor or hemichannel blockers to diminish microglial glutamate release without perturbing the physiological glutamate level. These drugs may give us a new therapeutic strategy against neurodegenerative diseases with minimum adverse side effects.
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PMID:Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. 1672 May 74