The Blood-Brain Barrier Is Disrupted under Stress

Several studies have demonstrated enhanced penetration of the brain by anti-AChEs under psychological stress. This stress-induced disruption of the BBB can explain some of the nervous system-associated sequelae reported by Gulf War veterans. Soldiers at the Gulf were exposed to unknown doses and combinations of various harmful xenobiotics.

For prophylactic protection from the anticipated chemical warfare agents, which would have irreversibly blocked acetylcholinesterase (AChE), Gulf War soldiers were administered pyridostigmine, a reversible carbamate cholinesterase inhibitor. Pyridostigmine includes a quaternary ammonium group that under normal circumstances prevents its crossing the BBB. Thanks to this property, it is used routinely to treat peripheral neuromuscular junction deficiencies in patients with the autoimmune disease myasthenia gravis.

During peacetime clinical tests that involved healthy volunteers, pyridostigmine caused mild, primarily peripheral side effects. In contrast, during the Gulf War, pyridostigmine in the same dosage caused a significant increase in reported central nervous system (CNS) symptoms. Friedman and colleagues showed, in animal experiments, that the dose of pyridostigmine required to block 50% of brain AChE was 100-fold lower in stressed mice.

The sudden need for energy in the stressed brain suggests that the disruption of the BBB may be beneficial when neurons are overactivated. Nevertheless, BBB disruption may also allow toxic agents and unneeded proteins to penetrate the brain, which may impair brain functioning under stress. However, the linkage between neuronal excitability and the nature of those impairments is still largely obscure. AChE inhibitors, which increase cholinergic signaling by preventing acetylcholine (ACh) hydrolysis, were reported to cause transient permeabilization of the BBB.

Revealing the molecular mechanisms underlying the links between cholinergic and other elements in BBB-associated cells should therefore contribute significantly toward our understanding of the mechanism(s) leading to BBB disruption under psychological stress. Because cholinergic neurotransmission is imbalanced following traumatic impacts, this question was addressed using transgenic mice overexpressing synaptic AChE.

Diffusion-weighted MRI showed impaired water diffusion and BBB functioning, and DNA microarray analyses demonstrated the enhanced production of multiple ion channels and the water channel aquaporin 4. Thus, persistent cholinergic imbalance may by itself cause BBB malfunctioning.