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High threshold for stress-induced activation of the heat shock transcription factor, Hsf1, may contribute to vulnerability of motor neurons to disease and limit efficacy of agents promoting expression of neuroprotective heat shock proteins (Hsps) through this transcription factor. Plasmid encoding a constitutively active form of Hsf1, Hsf1act, and chemicals shown to activate Hsf1 in other cells were investigated in a primary culture model of familial amyotrophic lateral sclerosis. Hsf1act and the Hsp90 inhibitor, geldanamycin, induced high expression of multiple Hsps in cultured motor neurons and conferred dramatic neuroprotection against SOD1G93A in comparison to Hsp70 or Hsp25 alone. Two other Hsp90 inhibitors, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and radicicol, and pyrrolidine dithiocarbamate induced robust expression of Hsp70 and Hsp40 in motor neurons, but at cytotoxic concentrations. 17-AAG, which penetrates the blood–brain barrier, has exhibited a higher therapeutic index than geldanamycin, but this may not be the case when activation of Hsf1 in neurons is targeted. |
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