Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade

Abstract

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.

Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

“…This observation is also consistent with data obtained from DAT-KO mice in which DA receptors are continuously stimulated. In this regard, our results differ from previous reports of a D2 receptor activation of Akt and inactivation of GSK-3␤ after short-term exposure of cell cultures to DA agonists (40)(41)(42) or within 15 min after treatment of mice with cocaine (40) or amphetamine (43). Further detailed studies of DA receptor signaling at different time points after stimulation will be necessary to explain these discrepancies.…”

“…Indications are that DA receptors may not have the same signaling characteristics in different model systems. For instance, stimulation of D2 receptor has been shown to enhance inositol signaling in PC12 cells and to reduce it in rat lactotroph cells (41,42,44). Such differences in signaling may be explained by the coupling of DA receptors to different signaling machinery in different model systems or in response to different artificial DA agonists (41).…”

Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

“…1) Glutamate is a neurotransmitter with roles such as longterm potentiation and synaptic plasticity of the brain via Nmethyl D-aspartate receptors (NMDA), 16) and is also a exitotoxin whose neurotoxicity has been associated with numerous neurodegenerative diseases, such as AD, 17) vascular dementia, 18) Parkinson disease 19) and amyotrophic lateral sclerosis. 20) The mechanism of glutamate-induced neuronal death has been extensively studied: glutamate induces neuronal death via stimulation of NMDA receptor through which Ca 2ϩ enters the cell and activates Ca 2ϩ -dependent nitric oxide (NO) synthase, resulting in excessive nitric oxide formation, production of radicals, mitochondrial dysfunction and cell death.…”

Protein-Protein Coupling/Uncoupling Enables Dopamine D2Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity

“…The ability of PI-3K to promote cell survival through the activation of protein kinase B/Akt provides a potential mechanism for the protective effects of quinpirole treatment (Franke et al, 1997;Hemmings, 1997;Marte and Downward, 1997;Cantley, 2002). Although several groups have reported that D 2 receptor activation may lead to PI-3K activation (Kihara et al, 2002;Nair et al, 2003), there have also been reports of AMPA receptors coupling to PI-3K (Man et al, 2003). Furthermore, our group has reported that dopamine D 1 receptors protect against NMDA-mediated excitotoxicity through enhancing the NR1-CaM-p85 subunit coupling that leads to the activation of PI-3K pathway (Lee et al, 2002a).…”