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

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 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.

Biomarkers in primary open angle glaucoma

“…Oxidative stress induces synthesis of AP 4 A (41) . In vivo, AP 4 A reduced translocation of mitochondrial cytochrome C, activation of cytoplasmic caspase-3, and cerebral infarction in ischemic cerebral cortex in vivo (42) . These data suggest that AP 4 A is protective, via anti-apoptotic mechanisms, against ischemic injury in cerebral cortex.…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…Inosine, as well as adenosine, reduced astroglial injury in ischemia, and it was suggested that adenosine was acting after breakdown to inosine (Haun et al, 1996). The diadenosine polyphosphate Ap 4 A protects against injury induced by ischemia in rat brain through actions at P1 adenosine receptors (Wang et al, 2003b).…”

Diadenosine Polyphosphate Analog Controls Postsynaptic Excitation in CA3-CA1 Synapses via a Nitric Oxide-Dependent Mechanism

“…Indeed, previous studies have indicated that Ap 4 A reduces ischemic injury in the CNS and heart (Khattab et al, 1998;Ahmet et al, 2000a,b;Wang et al, 2003). Recently, Ap 4 A has been shown to have strong neuroprotective properties mediated by P1 and P4 receptors in primary neuronal culture used as models for stroke and Parkinson's disease (Wang et al, 2003).…”