Telmisartan mediates anti-inflammatory and not cognitive function through PPAR-γ agonism via SARM and MyD88 signaling

Telmisartan (TM), an angiotensin II receptor I (AT1) blocker, has been reported to have agonist property with respect to PPAR-gamma. Activation of PPAR-gamma receptor by TM attenuated the lipopolysaccharide (LPS) mediated TLR4 central downstream inflammatory responses. However, the missing link between PPAR-gamma and TLR4 signaling with TM stimulation has not been clarified. Hence, the present study has been designed to evaluate the molecular mechanism involving PPAR gamma-TLR4 signaling with TM stimulation in LPS induced inflammatory model. LPS was administered in rats through ICV and the rats were treated with either PPAR-gamma antagonist GW9662 (GW) or TM or both. After 14 days of LPS administration, the rats were subjected to behavioral tests and their brains were isolated for blotting techniques. The protein study includes NF-kappa B, PPAR-gamma receptors, and their downstream proteins (MyD88 & SARM). The pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6) levels were measured by ELISA and cresyl violet staining in the hippocampus region to measure the neuroprotective activity. Results have shown that TM significantly increased the motor co-ordination, cognitive functions, and activated SARM and PPAR-gamma protein levels. Also, TM treatment decreased the NF-kappa B, MyD88 activation, and cytokines release in LPS rats. The co-administration of GW attenuated the TM responses in the parameters studied except cognitive functions. TM (10 mg/kg) has significantly reduced the LPS mediated inflammatory responses. This resulted in effective regeneration of hippocampal neurons as observed by cresyl violet staining. It can be concluded that the activation of PPAR-gamma receptors may increase the SARM and decrease the MyD88 and NF-kappa B expression. This negative regulation of SARM dependent inflammation control could be a possible mechanism for TM anti-neuroinflammatory activity. This study of TM in neuro-inflammatory model may further confirm the dual activities of TM that controls hypertension and cognition through AT1 blockade and also attenuates neuro-inflammation via PPAR-gamma agonistic property. (C) 2015 Elsevier Inc. All rights reserved.