Adenosine and blood flow regulatory mechanisms in hippocampal ischemia



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Texas Tech University


According to the National Institutes of Health (NIH), stroke affects more than 700,000 people annually, making it the third leading cause of death and the most common cause of adult disability in the United States. The success of medical intervention after a stroke depends on its being started soon after the insult. Defined as an acute neurological disorder caused by disturbances of the cerebral blood supply, stroke can rapidly lead to the development of ischemic brain tissue that is comprised of a nonviable, necrotic core surrounded by a penumbral region. Although functionally depressed, the penumbral region remains metabolically intact making it potentially salvageable during the post-ischemic therapeutic window. As such, it is considered a promising target for acute therapeutic intervention. The limited success of current early interventions, however, argues for a greater understanding of the regulatory mechanisms governing the physiology of the ischemic brain.

Of particular interest are the regulatory mechanisms governing neuronal function and blood flow within the ischemic hippocampus. An integral part of the limbic system that is involved in the processing of short-term memory, the hippocampus is a bilateral structure that is exquisitely sensitive to hypoxia and/or ischemia. It is well established that an early response to cerebral hypoxic and/or ischemic conditions is a reversible inhibition of evoked synaptic potentials. The suppression of synaptic function is thought to serve as a neuroprotective mechanism to reduce energy expenditure during metabolic stress, i.e. hypoxia/ischemia. There is substantial evidence in in vitro preparations that the initial reversible loss of synaptic activity during exposure to hypoxia or ischemic-like conditions in the hippocampus is due to the release of endogenous adenosine acting at neuronal Ai receptors. Such roles for adenosine in in vivo preparations, however, have not been as convincingly demonstrated.

Using a rat model of unilateral common carotid artery occlusion coupled with hypoxia, this dissertation examines the regulatory mechanisms of hippocampal blood flow and the contribution of adenosine to the early hypoxic/ischemic inhibition of synaptic transmission in an in vivo model of ischemic penumbra, and additionally examines the role of adenosine in the initiation of a post-ischemic, anti-apoptotic signal transduction pathway, Akt/Protein Kinase B. Animals were placed in a stereotaxic apparatus and evoked excitatory postsynaptic potentials (fEPSPs) were recorded from CAl of the rat hippocampus. Additionally, body temperature, systemic blood pressure, arterial blood gases, and hippocampal blood flow using laser Doppler flowmetry were monitored during experiments. Akt/PKB activation was examined using Western blot analysis.

We demonstrate for the first time in an in vivo preparation, that A1 receptor activation plays a central role in the early hypoxic-ischemic depression of the evoked hippocampal synaptic potentials. Moreover, we demonstrate that while hypoxia is a potent stimulus for the adenosine-mediated depression of the synaptic potentials in vitro, reduced hippocampal tissue p02 alone does not appear to be sufficient to induce an adenosine-mediated depression of synaptic transmission in vivo. There must be, it seems, an accompanying reduction in local hippocampal blood flow. Moreover, the adenosine A1- mediated depression of synaptic depression occurs in proportion to reductions in local cerebral blood flow over a wide range of flows typical of penumbra. We also demonstrated that A] receptor activation leads to the activation of the neurotrophic/anti-apoptotic protein kinase Akt/Protein Kinase B (PKB). This result suggest that Akt/PKB activation may play a heretofore unappreciated role in adenosine A1-mediated signal transduction and, therefore, in adenosine A 1-mediated neuroprotection.

We conclude from this work that adenosine acts as both an endogenous mediator and a sensitive indicator of penumbral conditions throughout the range of penumbral blood flows, and is an important mediator of the cellular response to survivable levels of ischemia.



Adenosine, Cerebral ischemia, Cerebral circulation, Blood flow, Hippocampus (Brain)