Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade.
Glutamate, one of the excitatory neurotransmitters, contributes to the neuronal death associated with neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and with ischemia. In Alzheimer's disease brains, there is a decreased number of dopamine D2 receptors, which might cause neuronal dysfunction or death. In the present study, bromocriptine exerted a protective effect against glutamate-induced cytotoxicity in rat cortical neurons. This neuroprotective effect was mediated via D2 receptors, because it was attenuated by domperidone, a D2 dopaminergic receptor antagonist. Another dopamine D2 agonist, quinpirole, also protected cells against glutamate toxicity. D2 agonists protected cells from calcium influx, nitric oxide, and peroxynitrite toxicity, which are thought to be the mediators of glutamate toxicity. The phosphatidylinositol 3 kinase (PI3K) inhibitor (LY294002) inhibited this neuroprotective effect of bromocriptine, in contrast to the mitogen-activated protein kinase kinase (MAPKK) inhibitor (PD98059), which did not counter the protective effect. Furthermore, Akt protein kinase, which is an effector of PI3K, was activated by bromocriptine, and the antiapoptotic protein Bcl-2 was up-regulated by bromocriptine treatment. These results suggest that D2 dopaminergic receptor activation plays an important role in neuroprotection against glutamate cytotoxicity and that the up-regulation of Bcl-2 expression via the PI3K cascade is, at least partially, involved in this effect.
Kihara
Takeshi
T
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Shimohama
Shun
S
Sawada
Hideyuki
H
Honda
Kazuhiro
K
Nakamizo
Tomoki
T
Kanki
Rie
R
Yamashita
Hiroshi
H
Akaike
Akinori
A
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D018491:Dopamine Agonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D001971:Bromocriptine; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D007476:Ionophores; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D019257:Quinpirole; D017448:Receptors, Dopamine D2; C494920:Akt1 protein, rat