Pharmacologically increasing microtubule acetylation corrects stress ‐exacerbated effects of organophosphates on neurons

Abstract Many veterans of the 1990–1991 Gulf War contracted Gulf War Illness, a multi‐symptom disease that primarily affects the nervous system. Here we treated cultures of human or rat neurons with diisopropylfluorophosphate (DFP), an analog of sarin, one of the organophosphate toxicants to which the military veterans were exposed. All observed cellular defects produced by DFP were exacerbated by pretreatment with corticosterone or cortisol, which, in the rat and human neurons respectively, serves in our experiments to mimic the physical stress endured by soldiers during the war. To best mimic the disease, DFP was used below the level needed to inhibit acetylcholinesterase. We observed a diminution in the ratio of acetylated to total tubulin that was correctable by treatment with tubacin, a drug that inhibits HDAC6, the tubulin deacetylase. The reduction in microtubule acetylation was coupled with deficits in microtubule dynamics, which were correctable by HDAC6 inhibition. Deficits in mitochondrial transport and dopamine release were also improved by tubacin. Thus, various negative effects of the toxicant/stress exposures were at least partially correctable by restoring microtubule acetylation to a more normal status. Such an approach may have therapeutic benefit for individuals suffering from GWI or other neurological disorders linked to organophosphate exposure. Synopsis An organophosphate surrogate for sarin elicits negative effects on microtubule stability, organel...
Source: Traffic - Category: Research Authors: Tags: ORIGINAL ARTICLE Source Type: research