Neuroprotective effects on Hippocampal neurons

Neuroprotective effects on Hippocampal neurons - Journal of...

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Effects of Neuroprotective Cocktails on Hippocampal Neuron Death in an In Vitro Model of Cerebral Ischemia Richard Liniger, Robert Popovic, Breandan Sullivan, George Gregory, and Philip E. Bickler Department of Anesthesia, University of California at San Francisco, San Francisco, California Summary: Cocktails of neuroprotectants acting at different parts of the ischemic injury cascade may have advantages over single agents. This study investigated, singly and in combination, the neuroprotective efficacy of an energy substrate (3.5 mM fructose 1,6- bisphosphate, FBP), an antagonist of NMDA receptors (1 and 10 m M MK-801), a free-radical scavenger (100 m M ascorbate), an adenosine A1 receptor agonist (10 m M 2-chloroadenosine), and an inhibitor of neurotransmission (2% isoflurane). These agents were evaluated for their ability to prevent loss and morphologic damage of CA1 neurons in rat hippocampal slices when these agents were administered during 30 minutes in vitro ischemia (combined oxygen/glucose deprivation at 37°C) followed by 5 hours of recov- ery. Ten m M MK-801, alone or in combination with the other compounds, prevented loss of CA1 neurons and preserved their histologic appearance. Isoflurane, which prevents glutamate receptor-dependent cell death in this model, was also protective. Protection against neuron loss was also found when a subtherapeutic concentration of MK-801 (1 m M) was combined with 2-chloroadenosine (which indirectly causes NMDA receptor suppression), but not FBP or ascorbate. The authors conclude that in this model, the strategy of antagonizing NMDA receptors appears more protective than fructose-1,6- bisphosphate, 2-chloroadenosine or ascorbate. Key Words: Cerebral ischemia— Hippocampal slices—Neuroprotection—Fructose-1,6-bisphosphate—MK-801— Ascorbate—2-chloroadenosine—Isoflurane Currently, the optimal therapy for reducing brain injury from cerebral ischemia is uncertain. Over the years, strat- egies aimed at specific aspects of the injury cascade have been tested in various in vitro and intact animal models of focal or global cerebral ischemia. Some of these strat- egies have included support of energy metabolism with endogenous glycolytic pathway substrates such as fruc- tose-1,6-bisphosphate (FBP) (1,2), antioxidant/free radical scavenging strategies with steroids, ascorbate, or alpha- tocopherol, and anti-inflammatory strategies with various drugs (3). Another group of strategies aims to prevent ion translocation (such as Ca 2+ and Na + influx) through an- tagonism of glutamate receptors, antagonism of glutamate release, blockade of voltage-gated calcium channels, blockade of voltage-gated sodium channels, or by activa- tion of adenosine receptors (4,5). Other strategies have included agents that increase inhibitory neurotransmission in the CNS (barbiturates, volatile anesthetics, and benzo- diazepines), which aim to decrease neuronal excitability and energy consumption (6,7). More recently, therapies
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Neuroprotective effects on Hippocampal neurons - Journal of...

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