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August 1996
Volume 60 |
Number 8
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| Molecular Biology
and the Brain |
Paula M. Bokesch, M.D.
Anesthetic management of patients subjected to brain hypoperfusion
or ischemia, as occurs during neurosurgery, carotid artery surgery
and cardiopulmonary bypass, has historically focused on improving
cerebral blood flow or decreasing cerebral metabolic rate. In
the last few years, there has been growing enthusiasm for an alternative
therapeutic approach directed at improving the intrinsic ability
of brain parenchyma to withstand ischemia and abnormal perfusion.
Glutamate and related amino acids are the principal excitatory
neurotransmitters in the brain and are essential for central neural
processing for cognition, memory, sensation and movement [Figure
1]. Large amounts of glutamate are present in the brain, stored
in presynaptic terminals and in glia. Glutamate exerts its physiologic
action via several distinct families of glutamate receptors located
on the postsynaptic neurons. Each class of receptor has a distinct
pharmacology and physiology and is named for the agonist compounds
that are specific in eliciting a specific physiologic response.
Accordingly, they are known as N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic
acid (AMPA) and kainate receptors. All of these receptors are
ligand-gated ion channels or ionotropic receptors: when glutamate
is released from nerve terminals and binds with postsynaptic ionotropic
receptors, it opens the cation channels, resulting in membrane
depolarization and a subsequent action potential. Glutamate receptors
are located on all neurons in the brain. Glutamate neurotransmission
plays a crucial role in cortical and hippocampal cognitive function,
pyramidal and extrapyramidal motor function, cerebellar function
and sensory function.1
The same receptors for glutamate and other excitatory amino acids
(EAAs) that mediate normal neuronal depolarization can also be
responsible for neuronal injury when cells are deprived of oxygen
or become energy-starved due to inadequate perfusion. Prolonged
stimulation of EAA receptors of either NMDA or non-NMDA types
eventually results in the death of most neurons. Olney et al.
coined the term "excitotoxicity" for excessive activation
of glutamate receptors triggered when neurons are deprived of
oxygen and energy supplies; this occurs in a variety of pathologic
conditions, including stroke, hypoglycemia, seizures and neurodegenerative
disorders.2 Hypoxia/ischemia induces
a large increase in extracellular glutamate through both excessive
presynaptic glutamate release and decreased removal of glutamate
from the synaptic cleft. Excess glutamate causes calcium ions
to flow into neurons through channels opened by NMDA and non-NMDA
receptors. Calcium is a major second messenger in neurons and
plays an important role in the regulation of many enzymatic pathways.
Increased intracellular calcium also leads to a rapid increase
(within minutes) of the mRNAs for the immediate early genes (early
response genes) or transcription factors. What follows is a complex
series of events that stimulate gene expression (late response
genes) and protein synthesis activating enzymes, proteases and
lipases, which then destroy cell membranes. Additional destruction
occurs from the release of nitric oxide and free radicals.1
Ischemia and reperfusion induce increased synthesis of a number
of specific proteins, including heat shock protein (HSP), c-fos
protein and glial fibrillary acidic protein (GFAP). Expression
of these proteins is regulated, in part, by calcium influx through
NMDA receptor activation. Although the significance of induction
of these proteins is not well-understood, their induction has
been associated with increased resistance to ischemic injury (HSP),
cell regeneration (c-fos) and glial response toward the regenerative
process (GFAP). Furthermore, using molecular biology techniques,
these proteins can be assayed to assess the extent of brain injury
and potential therapeutic interventions.3
Presently, drugs are being developed that target every step of
this excitotoxic cascade: glutamate-release inhibitors, competitive
and noncompetitive NMDA receptor antagonists, sodium and calcium
channel blockers, protein kinase inhibitors and free-radical scavengers.
Induction of genes that make neurotrophic factors, the neuron-nurturing
proteins, is another therapeutic approach. Compounds directed
at the NMDA subclass of the glutamate receptor have shown promising
results in clinical trials with conscious stroke patients.4
Whereas they cause psychotic symptoms and hypertension in awake
patients, these side effects may not be significant in anesthetized
patients requiring neuroprotection.
Therefore, pre-emptive application of these novel therapeutic
agents in anesthetized patients prior to neurosurgery, carotid
artery surgery or cardiopulmonary bypass may be highly beneficial.
References:
1. Greenamyre JT, Porter RH. Anatomy and physiology
of glutamate in the CNS. Neurology. 1994; 44:S7-S13.
2. Olney JW, Ho OL, Rhee V. Cytotoxic effects
of acidic and sulphur containing amino acids on the infant mouse
central nervous system. Exp Brain Res. 1971; 14:61-76.
3. Bokesch PM, Marchand JE, Connelly CS, et al.
Dextromethorphan inhibits ischemia-induced c-fos expression and
delayed neuronal death in hippocampal neurons. Anesthesiology.
1994; 81:470-477.
4. Albers GW, Goldberg MP, Choi DW. N-methyl-D-aspartate
antagonists: Ready for clinical trial in brain ischemia? Ann
Neurol. 1989; 25(4):398-403.
Paula M. Bokesch, M.D., is Staff Anesthesiologist,
Department of Cardiothoracic Anesthesia, Cleveland Clinic Foundation,
Cleveland, Ohio.
E-mail the author.
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