Alpha-5 GABA type A receptors linked to anesthesia-related memory loss

A drug targeting one specific receptor may provide the first effective approach to treatment for the common problem of memory loss after surgery and anesthesia, according to an experimental study in the April issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).

The "proof-of-concept" study shows that alpha-5 GABA type A receptors play an essential role in the development of specific memory problems after anesthesia, "and that these receptors can be targeted to restore memory even after the anesthetic has been eliminated." The lead author was Agneiska A. Zurek, BSc, of University of Toronto.

Anesthesia-Related Memory Loss Linked to Specific Receptors
The researchers performed a series of experiments in mice to assess the mechanisms of memory loss after general anesthesia. The study focused on the alpha-5 GABA type A receptors, which are the principal target for most anesthetics.

Previous studies had also suggested that these receptors play a role in certain types of anesthesia-related memory impairment. The experiments included genetically engineered mice that lacked the alpha-5 GABA type A receptors. Behavioral tests were used to assess specific types of memory function.

Exposure to isoflurane—a widely used general anesthetic—caused significant impairments in short-term memory in normal mice. But in mice without the alpha-5 GABA type A receptors, memory function was unaffected.

The memory deficits were specific to short-term memory, but did not affect "working memory." If the effects are similar in humans, "Our results predict that patients exposed to isoflurane could exhibit normal recall for immediate events that are accessible to working memory but might exhibit deficits in recall for events after a longer delay," the researchers write.

Could Receptor-Blocking Drugs Restore Memory after Anesthesia?
The study also evaluated the effects of an experimental drug—called L-655,708—that blocks the alpha-5 GABA type A receptors. Unexpectedly, treatment with L-655,708 completely eliminated the anesthesia-related memory deficits. This was so even though treatment wasn't given until 24 hours after isoflurane exposure—by which time there was little or not concentration of anesthetic remaining in the brain. Even without treatment, the impairment in short-term memory resolved by 72 hours after anesthesia.

The experiments raise new questions about how anesthesia-related memory impairment occurs. Anesthesiologists know that general anesthetics can cause persistent memory problems—for example, nearly half of elderly patients undergoing heart surgery still have cognitive deficits by the time they leave the hospital. "Such cognitive deficits are associated with poor long-term outcome, yet no specific treatments have been developed," Zurek and coauthors add.

The new findings strongly suggest that the alpha-5 GABA type A receptors are "necessary for the development" of anesthesia-related memory deficits. They also suggest that drugs to block those receptors are a "plausible strategy for reversing memory deficits after general anesthesia," the researchers write.

Some related drugs are already in preliminary studies for the treatment of Alzheimer's disease, Zurek and coauthors note. However, the emphasize that their study raises several issues requiring further research—starting with a clearer understanding of the mechanisms leading to anesthesia-related memory impairments.