Peroxisome Proliferator-Activated Receptors: “Key” Regulators of Neuroinflammation after Traumatic Brain Injury

Figure 2

Working hypothesis of PPAR-mediated mechanisms of neuroprotection after traumatic brain injury. The neuropathological sequelae of head injury include the posttraumatic activation of NFκB-dependent inflammatory genes. The transcription of neuroinflammatory mediators in the injured brain induces and perpetuates the intracranial inflammatory response and leads to formation of brain edema and adverse outcome. Activation of PPARs by binding of synthetic ligands, such as the PPAR𝛼 agonist fenofibrate, leads to inhibition of NFκB and of downstream transcribed proinflammatory and proapoptotic mediators. In addition, cannabinoids have a dual neuroprotective function, (1) by acting as ligands to PPARs and (2) by inhibiting “key” mediators of neuroinflammation and apoptosis, such as tumor necrosis factor (TNF). The combination therapy of synthetic PPAR agonists and cannabinoids may represent the long sought pharmacological “golden bullet” for the treatment of traumatic brain injury in the future.