Reduction in Cerebral Ischemic Injury in the Newborn Rat by Potentiation of Endogenous Adenosine

Abstract

Because of ontogenic influences on the pathophysiologic mechanisms of brain injury in the perinatal brain, and in particular, the incomplete development of adenosine receptor systems, we investigated the potential for adenosine to provide cerebroprotection in a well established newborn rat model of hypoxiaischemia. Fifteen litters of postnatal d 7 animals were subjected to unilateral carotid ligation and exposure to hypoxia (8% oxygen) for 3 h. Immediately after hypoxia-ischemia, animals received either the adenosine deaminase inhibitor deoxycoformycin (DCF; 2.5 mg/kg intraperitoneally) or the adenosine uptake inhibitor propentofylline (PPF; 10 mg/kg intraperitoneally); paired littermates received an equivalent volume of normal saline. On postnatal d 14, injury or protection was assessed by differences in hemispheric weights, morphometric determinations of infarct area, and histopathologic analyses. DCF resulted in a 34% (p = 0.02) and 31% ( p = 0.03) reduction in hemispheric weight disparities and infarct area, respectively; for PPF, these reductions were 46% ( p = 0.03) and 32% ( p = 0.04), Although the brain of the newborn exhibits a higher tolerance to ischemia than that of the adult, morbidity and mortality from hypoxic-ischemic encephalopathy in the perinatal period remain high (1). Although the general pathophysiologic mechanisms underlying cerebral ischemic injury are probably similar between age groups, the unique characteristics of energy and glucose metabolism (2), glutamate receptor physiology (3, 4), and vascular regulation (5, 6) in the newborn brain may dictate separate therapeutic regimens for affected neonates relative to adults.In recent years, experimental evidence has accumulated from adult animal models attesting to the neuroprotective properties of the purine nucleoside adenosine in the setting of Received February 3, 1995; accepted April 6, 1995 7 for review), and the mechanistic basis for such an adenosine-mediated reduction in ischemic brain injury has been outlined (8). Ontogenic studies of the brains of fetal and newborn animals indicate that the requisite metabolic enzymes and transporters for adenosine are fully matured at birth or earlier (9-12). There is also consistent evidence that cerebral adenosine production increases in response to perinatal hypoxia-ischemia (13-16). Although cerebral vessels in fetal and newborn animals exhibit the characteristic vasodilatative response to adenosine (17, 18), significant development of neuronal adenosine receptors, particularly in terms of density and coupling to second messengers, may occur postnatally (12,19,20). Thus, adenosinebased treatments may not provide therapeutic efficacy against cerebral hypoxia-ischemia in the perinatal period. To address this possibility, we used two different drugs to determine whether potentiating endogenous adenosine would confer cerebroprotection in a neonatal model of hypoxia-ischemia.

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…The activation of A 1 Rs might even be detrimental for the immature brain, since A 1 R activation inhibits neurite outgrowth [351,352], which may be the reason for the ability of caffeine and A 1 R antagonists to prevent the prevalent condition of periventricular leukomalacia in newborns [346]. Interestingly, the acute increase of extracellular adenosine affords neuroprotection against ischemic insults in the immature brain [353]. This may make sense if one considers that the role of A 2A Rs in controlling neuronal damage is also the opposite in the immature brain and in adult animals.…”

Adenosine Produces Changes in Cerebral Hemodynamics and Metabolism as Assessed by Near-Infrared Spectroscopy in Late-Gestation Fetal Sheep in Utero

“…Plasma adenosine levels are also higher in hypoxemic, acidotic growth-retarded human fetuses than in appropriately grown fetuses (3). This may be seen as a direct consequence of the hypoxemia, but there is also the possibility that elevated tissue and plasma adenosine may form part of a protective fetal adaptation aimed at matching oxygen demand to availability (4,5). Adenosine acting via A2 receptors is known to cause vasodilatation both in the peripheral and cerebral vascular beds, which improves cerebral blood flow and, thus, cerebral DO 2 (6,7).…”

Deletion of presynaptic adenosine A1 receptors impairs the recovery of synaptic transmission after hypoxia

“…Neuronal damage in these conditions is primarily caused by excessive release of glutamate (Simon et al, 1984;Obrenovitch and Urenjak, 1997;Sattler et al, 2000), and adenosine protects neurons by activating A 1 receptors that reduce glutamate release and NMDA receptor activation (Fredholm, 1997;Sweeney, 1997;de Mendonca et al, 2000). Accordingly, protection against hypoxia and ischemia can be achieved by increasing extracellular levels of adenosine through inhibition of adenosine degradation or reuptake (Gidday et al, 1995;Miller et al, 1996;Jiang et al, 1997 antagonists or increased breakdown of extracellular adenosine exacerbates neuronal loss from hypoxia and ischemia (Sweeney, 1997;de Mendonca et al, 2000).In the CA1 region, hypoxia and ischemia disrupt synaptic transmission, protein synthesis, maintenance of ATP levels, cytoskeletal integrity, and neuronal morphology (Lipton, 1999;Wang et al, 1999). However, hypoxia also induces release of adenosine (Dale et al, 2000;Frenguelli et al, 2003) which rapidly depresses synaptic transmission and neuronal firing (Lipton and Whittingham, 1979;Fowler, 1989;Gribkoff et al, 1990).…”