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Israeli Study
Pyridostigmine brain penetration under stress enhances neuronal excitablity and induces early immediate transcriptional response
Alon Friedman, Daniela Kaufer, Joshua Shemer, Israel Hendler, Hermona Soreq & Ilan Tur-Kaspa
Department of Biological Chemistry, the Life Sciences Institute, the Hebrew University, Jerusalem 91904, Israel Medical Corps, Israel Defense Forces, P.O. Box 02419, Israel Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer 52621, Israel
The views expressed are those of the authors and are not be construed as official policy of the Medical Corps, Israel Defense Forces. Correspondence should be addressed should be addressed to A.F.
Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Pyridostigmine is also recommended by most Western armies for use as pretreatment under threat of chemical warfare, because of its protective effect against organophosphate poisoning. 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 functions. 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 symptoms. This increase was not due to enhanced absorption (or decreased elimination) of the drug, because the inhibition efficacy of serum butyrylcholinesterase was not modified. Because previous animal studies have shown stress-induced disruption of the blood-brain barrier, an alternative possibility was that 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 stress), an increase in blood-brain barrier permability reduced the pyridostigmine dose required to inhibit mouse brain AChE activity by 50% to less thatn 1/199th of the usual dose. Under these conditions, peripherally adminstered 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.
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