Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain

Yun Wang, Chen Fu Chang, Marisela Morales, Yung Hsiao Chiang, Brandon K. Harvey, Tsung Ping Su, Li I. Tsao, Suyu Chen, Christoph Thiemermann

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Diadenosine tetraphosphate (AP4A), an endogenous diadenosine polyphosphate, reduces ischemic injury in the heart. In this study, we report the potent and protective effects of AP4A in rodent models of stroke and Parkinson's disease. AP4A, given intracerebroventricularly before middle cerebral artery (MCA) ligation, reduced cerebral infarction size and enhanced locomotor activity in adult rats. The intravenous administration of AP4A also induced protection when given early after MCA ligation. AP4A suppressed terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) induced by hypoxia/reperfusion in primary cortical cultures, and reduced both ischemia-induced translocation of mitochondrial cytochrome c and the increase in cytoplasmic caspase-3 activity in vivo. The purinergic P2/P4 antagonist di-inosine pentaphosphate or P1-receptor antagonist sulfonylphenyl theophylline, but not the P2-receptor antagonist suramin, antagonized the effect of AP4A, suggesting that the observed protection is mediated through an antiapoptotic mechanism and the activation of P1- and P 4-purinergic receptors. AP4A also afforded protection from toxicity induced by unilateral medial forebrain bundle injection of 6-hydroxydopamine (6-OHDA). One month after lesioning, vehide-treated rats exhibited amphetamine-induced rotation. Minimal tyrosine hydroxylase immunoreactivity was detected in the lesioned nigra or striatum. No KCl-induced dopamine release was found in the lesioned striatum. All of these indices of dopaminergic degeneration were attenuated by pretreatment with AP4A. In addition, AP4A reduced TUNEL in the lesioned nigra 2 d after 6-OHDA administration. Collectively, our data suggest that AP4A is protective against neuronal injuries induced by ischemia or 6-OHDA through the inhibition of apoptosis. We propose that AP4A may be a potentially useful target molecule in the therapy of stroke and Parkinson's disease.

Original languageEnglish
Pages (from-to)7958-7965
Number of pages8
JournalJournal of Neuroscience
Volume23
Issue number21
Publication statusPublished - Aug 27 2003
Externally publishedYes

Fingerprint

Oxidopamine
Ischemia
Uridine Triphosphate
Middle Cerebral Artery
Wounds and Injuries
Brain
Ligation
Parkinson Disease
Stroke
Heart Injuries
Medial Forebrain Bundle
Purinergic Receptors
Suramin
Polyphosphates
Inosine
DNA Nucleotidylexotransferase
Cerebral Infarction
Tyrosine 3-Monooxygenase
Amphetamine
Locomotion

Keywords

  • Apoptosis
  • Diadenosine tetraphosphate
  • Ischemia
  • Parkinson's disease
  • Protection
  • Repair
  • Stroke

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Wang, Y., Chang, C. F., Morales, M., Chiang, Y. H., Harvey, B. K., Su, T. P., ... Thiemermann, C. (2003). Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain. Journal of Neuroscience, 23(21), 7958-7965.

Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain. / Wang, Yun; Chang, Chen Fu; Morales, Marisela; Chiang, Yung Hsiao; Harvey, Brandon K.; Su, Tsung Ping; Tsao, Li I.; Chen, Suyu; Thiemermann, Christoph.

In: Journal of Neuroscience, Vol. 23, No. 21, 27.08.2003, p. 7958-7965.

Research output: Contribution to journalArticle

Wang, Y, Chang, CF, Morales, M, Chiang, YH, Harvey, BK, Su, TP, Tsao, LI, Chen, S & Thiemermann, C 2003, 'Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain', Journal of Neuroscience, vol. 23, no. 21, pp. 7958-7965.
Wang, Yun ; Chang, Chen Fu ; Morales, Marisela ; Chiang, Yung Hsiao ; Harvey, Brandon K. ; Su, Tsung Ping ; Tsao, Li I. ; Chen, Suyu ; Thiemermann, Christoph. / Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain. In: Journal of Neuroscience. 2003 ; Vol. 23, No. 21. pp. 7958-7965.
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AB - Diadenosine tetraphosphate (AP4A), an endogenous diadenosine polyphosphate, reduces ischemic injury in the heart. In this study, we report the potent and protective effects of AP4A in rodent models of stroke and Parkinson's disease. AP4A, given intracerebroventricularly before middle cerebral artery (MCA) ligation, reduced cerebral infarction size and enhanced locomotor activity in adult rats. The intravenous administration of AP4A also induced protection when given early after MCA ligation. AP4A suppressed terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) induced by hypoxia/reperfusion in primary cortical cultures, and reduced both ischemia-induced translocation of mitochondrial cytochrome c and the increase in cytoplasmic caspase-3 activity in vivo. The purinergic P2/P4 antagonist di-inosine pentaphosphate or P1-receptor antagonist sulfonylphenyl theophylline, but not the P2-receptor antagonist suramin, antagonized the effect of AP4A, suggesting that the observed protection is mediated through an antiapoptotic mechanism and the activation of P1- and P 4-purinergic receptors. AP4A also afforded protection from toxicity induced by unilateral medial forebrain bundle injection of 6-hydroxydopamine (6-OHDA). One month after lesioning, vehide-treated rats exhibited amphetamine-induced rotation. Minimal tyrosine hydroxylase immunoreactivity was detected in the lesioned nigra or striatum. No KCl-induced dopamine release was found in the lesioned striatum. All of these indices of dopaminergic degeneration were attenuated by pretreatment with AP4A. In addition, AP4A reduced TUNEL in the lesioned nigra 2 d after 6-OHDA administration. Collectively, our data suggest that AP4A is protective against neuronal injuries induced by ischemia or 6-OHDA through the inhibition of apoptosis. We propose that AP4A may be a potentially useful target molecule in the therapy of stroke and Parkinson's disease.

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