Abstract W P249: Agonism of Transient Receptor Potential Vanilloid Member 1 Induces a Protective Heat Shock Response in the Brain
Background: There is a lack of widely applicable treatments of stroke. One of the potential new treatment strategies is the induction of heat shock proteins (HSPs), such as Hsp27 and Hsp70, in the brain, which was shown to confer neuroprotection from ischemia. In epithelial cells, HSPs were shown to be induced by agonists of the Transient Receptor Potential Vanilloid Member 1 ion channel (TRPV1), also known as the heat and capsaicin receptor. Therefore, our overall hypothesis is that systemic administration of TRPV1 agonist dihydrocapsaicin (DHC) induces HSPs in the brain cortical neurons and thus provides neuroprotection from stroke. In the present study we focus on the initial portion of the hypothesis, that TRPV1 agonism promotes HSP induction in the brain.
Methods: We determined relative expression of candidate HSP genes by quantitative real-time polymerase chain reaction after DHC treatment in cultured rat primary cortical neurons as well as in cortex tissue samples of in vivo DHC-treated wild-type and TRPV1 knock-out mice.
Results: First, we established that DHC injection (4 mg/kg i.p.) 4 hours before tissue harvest led to 3- and 5-fold upregulation of mRNA of the Hsp27 and Hsp70 respectively in the cortex of mice (compared to vehicle injection, n=3 mice per group). This effect was specific to TRPV1 channels, as it was absent in TRPV1 knock-out mice. Second, we determined that 3-hour DHC treatment led to upregulation of Hsp70 mRNA in cultured rat primary cortical neurons, which was dependent on the dose of DHC (1-1000 nM).
Conclusions: We present the first demonstration that systemic delivery of TRPV1 agonists promotes an upregulation of neuroprotective heat shock proteins in the brain. We have further demonstrated that cortical neurons have the capacity to respond to TRPV1 agonism directly rather than through other TRPV1-mediated physiologic responses. We propose that systemic delivery of TRPV1 agonists may offer a novel treatment option in the protection or recovery from ischemic stroke.
Author Disclosures: V.V. Feketa: None. A. Balasubramanian: None. Z. Cao: None. S.P. Marrelli: None.
This research has received full or partial funding support from the American Heart Association, SouthWest - Arkansas, Colorado, New Mexico, Oklahoma, Texas, Wyoming.
- © 2015 by American Heart Association, Inc.