Role of hippocampal serotonergic neurons in ischemic neuronal death

Nakata, Naoki; Suda, Hiroshi; Izumi, Junkichi; Tanaka, Yoshiaki; Ikeda, Yuichi; Kato, Harubumi; Itoyama, Yasuto; Kogure, Kyuya

doi:10.1016/s0166-4328(97)86073-1

Cited by 32 publications

(15 citation statements)

References 15 publications

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“…Among the different 5-HT receptors, the 5-HT1A receptor subtype seems to attenuate excitotoxicity. 5-HT1A agonists have been used to rescue cultured hippocampal neurons from glutamate-induced excitotoxicity and are also protective in ischemic neuronal cell death (Nakata et al, 1997;Harkany et al, 2001). Our results indicate that 5-HT1A receptor stimulation rescues both striatal and nigral neurons from the NMDA-induced degenerative process.…”

Section: Discussionmentioning

confidence: 99%

“…Stimulation of the 5-HT1A receptor may play a role in neuronal survival (Raymond et al, 2001). 5-HT1A receptor stimulation rescued cultured hippocampal neurons from glutamate-mediated excitotoxicity and protected against ischemic neuronal cell death (Nakata et al, 1997;Harkany et al, 2001). Interestingly, 5-HT1A receptor activation improved the motor complications in rodent and primate models of PD (Bibbiani et al, 2001).…”

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5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

Madhavan

Freed

Anantharam

et al. 2002

J Pharmacol Exp Ther

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Apoptosis and glutamate-mediated excitotoxicity may play a role in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we investigated whether stimulation of the 5-hydroxytryptamine 1A (5-HT1A) receptor attenuates N-methyl-D-aspartate-(NMDA) and 1-methyl-4-phenylpyridinium (MPP ϩ )-induced apoptotic cell death in cell culture models. A brief exposure (20 min) of M213-2O striatal cells to NMDA and glutamate produced a delayed increase in caspase-3 activity and DNA fragmentation in a dose-and time-dependent manner. NMDA-induced caspase-3 activity and DNA fragmentation were almost completely blocked by the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and (R)-5-fluoro-8 hydroxy-2-(dipropylamino)-tetralin (R-UH-301). Additionally, the protective effects of 8-OH-DPAT and R-UH-301 on NMDA-induced caspase-3 activation and apoptosis were reversed by pretreatment with the 5-HT1A antagonists N- [2-[4-(2-methoxyphenyl(WAY 100635) and S-UH-301, respectively. Similarly, doseand time-dependent increases in caspase-3 activity and DNA fragmentation were observed in rat primary mesencephalic neurons after a brief exposure to NMDA and glutamate. Caspase-3 activation and DNA fragmentation in primary mesencephalic neurons were almost completely inhibited by 8-OH-DPAT. This neuroprotective effect of 8-OH-DPAT was reversed by WAY 100635. Additionally, 8-OH-DPAT blocked tyrosine hydroxylase (TH)-positive cell death after NMDA exposure and also almost completely attenuated the NMDA-induced Ca 2ϩ influx in primary mesencephalic cultures. Furthermore, 8-OH-DPAT and R-UH-301 blocked apoptotic cell death in the primary mesencephalic neurons that were exposed to the Parkinsonian toxin MPP ϩ . Together, these results suggest that 5-HT1A receptor stimulation may be a promising pharmacological approach in the development of neuroprotective agents for PD.Parkinson's disease (PD) is a major neurodegenerative disorder with a lifetime incidence of 1 to 2%. The drug L-DOPA has been the gold standard PD treatment for more than three decades now and can bring considerable relief from the debilitating symptoms of the disease. However, its long-term use has several limitations, including severe fluctuations in effectiveness and drug-induced involuntary movements (Fahn, 1999;Carlsson, 2002). Importantly, L-DOPA simply compensates for the dopamine deficiency in Parkinson's patients and fails to attenuate the progression of the disease. Hence, novel neuroprotective agents designed to interfere with the basic pathogenic mechanism of cell death in PD are clearly needed.Excitotoxic mechanisms may contribute to the nigrostriatal degeneration in PD (Greenamyre, 1993;Olanow and Tatton, 1999). Glutamate binds to a variety of excitatory amino acid receptors, especially the NMDA receptor, leading to prolonged and excessive depolarization and neuronal activation resulting in the death of target neurons (Choi, 1988;

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

Madhavan

Freed

Anantharam

et al. 2002

J Pharmacol Exp Ther

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“…Stimulation of the 5-HT1A receptor may play a role in neuronal survival (Raymond et al, 2001;Madhavan et al, 2003). 5-HT1A receptor stimulation rescued cultured hippocampal neurons from glutamate-mediated excitotoxicity and protected against ischemic neuronal cell death (Nakata et al, 1997;Harkany et al, 2001;Madhavan et al, 2003). Previous studies have shown that 5-HT1A receptor stimulation can (Strosznajder et al, 1996;Matsuyama et al, 1997;Madhavan et al, 2003).…”

Section: Discussionmentioning

confidence: 98%

Neuroprotective effect of ziprasidone: Preliminary results compared to haloperidol

Çınar¹,

Karaoğlan²,

Mıdı³

et al. 2014

jecm

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Article HistoryReceived 21 / 02 / 2014 Accepted 10 / 05 / 2014Typical and atypical antipsychotic drugs are widely used to treat psychosis. The present study investigated whether ziprasidone, an atypical antipsychotic drug, has a neuroprotective effect on hippocampal neurons in rats with experimentallyinduced transient cerebral ischemia comparatively with haloperidol which is a typical antipsychotic. Transient cerebral ischemia was induced by 10-minute occlusion of bilateral carotis communis arteries. The rats were divided into four groups: Shamoperated control group (Group I), ischemia control group (Group II), haloperidol-treated group (Group III) and ziprasidone-treated group (Group IV). Following 10-minute ischemia, Group III received 1mg/kg haloperidol intramuscularly and Group IV received 2.5 mg/kg ziprasidone intraperitoneally. The animals were sacrificed on the seventh day following induced ischemia to determine the number of intact neurons at hippocampus and dentate gyrus to demonstrate the effects of ischemia and efficacy of the treatments administered. Surviving cell numbers were found in the sham operated group; 198, in the ischemia control group; 80, in the haloperidol-treated group; 185, in ziprasidonetreated group; 189. The groups showed significant difference in the comparison of the surviving cell numbers. However, the number of surviving cells did not significantly different between the ziprasidone and haloperidol-treated group. Previous studies with the ischemia model have demonstrated protective effects of haloperidol on hippocampal region. The findings of the present study show that ziprasidone, which is an atypical antipsychotic drug, may produce neuroprotective effects as potent as haloperidol, which is a typical antipsychotic drug.

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“…Other studies have shown that 5-HT 1A receptor stimulation protects against ischemic neuronal cell death (14,24). Although the cellular mechanisms underlying the neuroprotective effect of 5-HT 1A receptor activation remain unclear, a proposed mechanisms is the hyperpolarization of pyramidal neurons that inhibits the excitotoxicity by glutamate after cerebral ischemia (45).…”

Section: Discussionmentioning

confidence: 99%

Serotonin 5-HT1A receptor activation prevents phosphorylation of NMDA receptor NR1 subunit in cerebral ischemia

Salazar-Colocho

Rı́o

Frechilla

2007

J. Physiol. Biochem.

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The mechanisms involved in the neuroprotective effect of serotonin 5-HT1A receptor agonists on brain damage induced by ischemia remain to be fully elucidated. Given that serotonergic drugs may regulate N-methyl-D-aspartate (NMDA) receptor function, which is implicated in events leading to ischemia-induced neuronal cell death, this study sought to determine the effects of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on the levels of NMDA receptor NR1 subunit in gerbil hippocampus after transient global cerebral ischemia. Pretreatment with 8-OH-DPAT (1 mg/kg) prevented the neuronal loss in CA1 subfield 72 h after ischemia. NMDA receptor NR1 levels in whole hippocampus were not affected 24 h after ischemia, but the levels of the subunit phosphorylated at the protein kinase A (PKA) site, pNR1(Ser897), were significantly increased, and this increase was prevented by the same 8-OH-DPAT dose, a probable consequence of the increased phosphatase 1 (PP1) enzyme activity found in ischemic gerbils pretreated with the 5-HT1A receptor agonist. The results suggest that NR1 subunit phosphorylation plays a role in the neuroprotective effect of 8-OH-DPAT on cell damage induced by global cerebral ischemia in the gerbil hippocampus and support the potential interest of 5-HT1A receptor activation in the search for neuroprotective strategies.

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Role of hippocampal serotonergic neurons in ischemic neuronal death

Cited by 32 publications

References 15 publications

5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

Neuroprotective effect of ziprasidone: Preliminary results compared to haloperidol

Serotonin 5-HT1A receptor activation prevents phosphorylation of NMDA receptor NR1 subunit in cerebral ischemia

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