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The Journal of Neuroscience, August 27, 2003, 23(21):7958-7965

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Diadenosine Tetraphosphate Protects against Injuries Induced by Ischemia and 6-Hydroxydopamine in Rat Brain

Yun Wang,^1,2 Chen-Fu Chang,^1,2 Marisela Morales,¹ Yung-Hsiao Chiang,² Brandon K. Harvey,¹ Tsung-Ping Su,¹ Li-I Tsao,¹ Suyu Chen,¹ and Christoph Thiemermann³

¹National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, ²Triservice General Hospital, National Defense Medical Center, Taipei, 114 Taiwan, and ³William Harvey Research Institute, Queen Mary University, London, EC1 M 6BQ United Kingdom

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 anti-apoptotic mechanism and the activation of P₁- and P₄-purinergic receptors.

AP₄A also afforded protection from toxicity induced by unilateral medial forebrain bundle injection of 6-hydroxydopamine (6-OHDA). One month after lesioning, vehicle-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.

Key words: ischemia; stroke; Parkinson's disease; repair; protection; diadenosine tetraphosphate; apoptosis

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Received March 5, 2003; revised July 3, 2003; accepted July 7, 2003.

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