Candesartan, an Angiotensin II AT1-Receptor Blocker and PPAR-γ Agonist, Reduces Lesion Volume and Improves Motor and Memory Function After Traumatic Brain Injury in Mice

Abstract

Traumatic brain injury (TBI) results in complex pathological reactions, the initial lesion worsened by secondary inflammation and edema. Angiotensin II (Ang II) is produced in the brain and Ang II receptor type 1 (AT 1 R) overstimulation produces vasoconstriction and inflammation. Ang II receptor blockers (ARBs) are neuroprotective in models of stroke but little is known of their effect when administered in TBI models. We therefore performed controlled cortical impact (CCI) injury on mice to investigate whether the ARB candesartan would mitigate any effects of TBI. We administered candesartan or vehicle to mice 5 h before CCI injury. Candesartan treatment reduced the lesion volume after CCI injury by approximately 50%, decreased the number of dying neurons, lessened the number of activated microglial cells, protected cerebral blood flow (CBF), and reduced the expression of the cytokine TGFb1 while increasing expression of TGFb3. Candesartan-treated mice also showed better motor skills on the rotarod 3 days after injury, and improved performance in the Morris water maze 4 weeks after injury. These results indicate that candesartan is neuroprotective, reducing neuronal injury, decreasing lesion volume and microglial activation, protecting CBF and improving functional behavior in a mouse model of TBI. Co-treatment with a peroxisome proliferator-activated receptor-gamma (PPARg) antagonist significantly reduced some of the beneficial effects of candesartan after CCI, suggesting that PPARg activation may contribute to part or to all of the neuroprotective effect of candesartan. Overall, our data suggest that ARBs with dual AT 1 R-blocking and PPARg activation properties may have therapeutic value in treating TBI.

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

“…Mice with mild and severe TBI in this experiment confirmed previous reports [75][76][77][78] of transient impairments in motor coordination as measured on an accelerating rotarod, and here brain-injured males and females had equivalent performance (Fig. 4).…”

Hepatic Expression of Serum Amyloid A1 Is Induced by Traumatic Brain Injury and Modulated by Telmisartan

“…41 We have previously reported that the systemic administration of the ARB, candesartan, reduces cerebral cortical lesion volume and inflammation, and improves motor and cognitive behavior after TBI. 42 We found similar neuroprotective results after TBI with another ARB, telmisartan. 43 Telmisartan, a highly selective AT1R antagonist, has been reported to exert potent systemic antioxidative and anti-inflammatory effects.…”

“…42 Lesion volume was obtained by multiplying the sum of the lesion areas by the distance between sections, with between 9 and 15 brain sections required to bridge the lesion. Percentage lesion volume was calculated by dividing each lesion volume by the total ipsilateral hemisphere volume.…”

Autonomic and inflammatory consequences of posttraumatic stress disorder and the link to cardiovascular disease

“…Inhibition of the RAS with angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), which selectively block the AT 1 R, are, therefore, widely used for the treatment of hypertension and CVD. There is a growing body of evidence, however, demonstrating that the therapeutic actions of both ACE-Is and ARBs extend beyond blood pressure reduction (11,92,108) and may have beneficial effects on stress-related pathologies, such as PTSD and panic disorder (43,50).…”

“…Inhibition of the RAS with angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), which selectively block the AT 1 R, are, therefore, widely used for the treatment of hypertension and CVD. There is a growing body of evidence, however, demonstrating that the therapeutic actions of both ACE-Is and ARBs extend beyond blood pressure reduction (11,92,108) and may have beneficial effects on stress-related pathologies, such as PTSD and panic disorder (43,50).Chronic stress, as manifested with PTSD, induces activation of the RAS, leading to increased ANG II synthesis (86). Experimental studies have shown that immobilization stress in rats increases circulating levels of ANG II (18) and binding of brain AT 1 R. Inhibition of the RAS using ACE-Is and ARBs can reverse these affects (6,17,62,94).…”