Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response

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Abstract
Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis1. Pyridostigmine is also recommended by most Western armies for use as pretreatment under threat of chemical warfare, because of its protective effect against organophosphate poisoning2,3. Because of this drug's quaternary ammonium group, which prevents its penetration through the blood–brain barrier, the symptoms associated with its routine use primarily reflect perturbations in peripheral nervous system functions1,4. Unexpectedly, under a similar regimen, pyridostigmine administration during the Persian Gulf War resulted in a greater than threefold increase in the frequency of reported central nervous system symptoms5. This increase was not due to enhanced absorption (or decreased elimination) of the drug, because the inhibition efficacy of serum butyrylcholinesterase was not modified5. Because previous animal studies have shown stress–induced disruption of the blood–brain barrier6, an alternative possibility was that the stress situation associated with war allowed pyridostigmine penetration into the brain. Here we report that after mice were subjected to a forced swim protocol (shown previously to simulate stress7), an increase in blood–brain barrier permeability reduced the pyridostigmine dose required to inhibit mouse brain AChE activity by 50% to less than 1/100th of the usual dose. Under these conditions, peripherally administered pyridostigmine increased the brain levels of c–fos oncogene and AChE mRNAs. Moreover, in vitro exposure to pyridostigmine increased both electrical excitability and c–fos mRNA levels in brain slices, demonstrating that the observed changes could be directly induced by pyridostigmine. These findings suggest that peripherally acting drugs administered under stress may reach the brain and affect centrally controlled functions.