Hypoxic brain injury is a dreaded complication of anesthesia, surgery, and childbirth. A hypoxic insult activates a series of cellular pathways, resulting in apoptotic and necrotic cellular death. The long-term results often include devastating changes in short-term or working memory. The hippocampus, thought to be important in encoding working memory, is exquisitely sensitive to hypoxic damage. In an article in this issue of Anesthesia & Analgesia, Bekker et al. have identified a potential post hoc treatment in a rodent model of hypoxic brain injury (1). The authors have shown that treatment with the acetylcholinesterase inhibitor, physostigmine, ameliorates hypoxia-induced performance deterioration on a working memory task in rats (1).
Early hypoxia-induced injury is associated with enhanced release of the excitatory neurotransmitter, glutamate (2). This insult sets into motion complex cellular physiological pathways that result in deficits in several neurotransmitter systems, including cholinergic transmission (3,4). Defects in cholinergic neurotransmission in the brain may represent a final common pathway for memory defect and dementia. The cholinergic system in the brain includes both muscarinic and nicotinic receptors for acetylcholine, which plays a role in cortical arousal, attention to specific sensory stimuli and rejection of irrelevant input (5). Both nicotinic and muscarinic receptors are important in cognitive function. Nicotine improves cognitive deficits in schizophrenia, Attention Deficit Hyperactivity Disorder and Alzheimer’s disease. The muscarinic system is also important for cognitive function. High-dose muscarinic antagonists can induce cognitive dysfunction. To make matters more complicated, and yet more promising, there are multiple subtypes of each type of receptor for acetylcholine. The complexity of both systems adds to the promise for specific potential therapies. Highly potent, subtype-selective ligands then have the potential to induce the desired effect with fewer side effects. Diseases associated with dementia, including Alzheimer’s disease and Parkinson’s-associated dementia have cholinergic deficits that are treated with pro-cholinergic drugs (6). Hopefully, future preclinical studies will be able to identify the specific type of nicotinic or muscarinic receptor that is helpful in the setting of hypoxia, as specific activation might be more beneficial.
It would obviously be very desirable to have a treatment that could be used after a hypoxic insult or, prophylactically, in high risk cases. Importantly, in the study by Bekker et al., treatment with physostigmine was effective after the insult, suggesting that treatment could potentially occur after an unexpected injury rather than only prophylactically (1). However, it is important to remember that the authors have not done studies to demonstrate that they are treating a specific cholinergic insult induced by hypoxia. Neurotransmitter concentrations were not measured in this study. It is possible that enhanced activity of either the nicotinic, muscarinic systems or both could overcome deficits in other neurotransmitter systems induced by hypoxia. Less likely, the physostigmine treatment effect could result from changes in other unrelated physiological variables such as hemodynamic control. Nonetheless, these findings in an animal model should be assessed with cautious optimism. Physostigmine is a drug with a long history of human use and a good safety record. However, historically, several treatments for brain injury that have shown promise in preclinical work have failed in clinical trials (7,8). The importance of the problem mandates a continued search for viable treatments to test in clinical trials, including those focused on the cholinergic system.
1. Bekker A, Haile M, Gingrich K, Wenning L, Gorny A, Quartermain D, Blanck T. Physostigmine reverses cognitive dysfunction caused by moderate hypoxia in adult mice. Anesth Analg 2007;105:739–43
2. Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 2007;27:1129–38
3. Chleide E, Ishikawa K. Hypoxia-induced decrease of brain acetylcholine release detected by microdialysis. Neuroreport 1990;1:197–9
4. Gibson G, Duffy T. Impaired synthesis of acetylcholine by mild hypoxic hypoxia or nitrous oxide. J Neurochem 1981;36:28–33
5. Hasselmo ME, Giocomo LM. Cholinergic modulation of cortical function. J Mol Neurosci 2006;30:133–5
6. Perry E, Walker M, Grace J, Perry R. Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci 1999;22:273–80
7. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 2007;49:391–402
8. Stover JF, Pleines UE, Morganti-Kossmann MC, Stocker R, Kossmann T. Thiopental attenuates energetic impairment but fails to normalize cerebrospinal fluid glutamate in brain-injured patients. Crit Care Med 1999;27:1351–7