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

Abstract

Traumatic brain injury is characterized by neuroinflammatory pathological sequelae which contribute to brain edema and delayed neuronal cell death. Until present, no specific pharmacological compound has been found, which attenuates these pathophysiological events and improves the outcome after head injury. Recent experimental studies suggest that targeting peroxisome proliferator-activated receptors (PPARs) may represent a new anti-inflammatory therapeutic concept for traumatic brain injury. PPARs are “key” transcription factors which inhibit NFκB activity and downstream transcription products, such as proinflammatory and proapoptotic cytokines. The present review outlines our current understanding of PPAR-mediated neuroprotective mechanisms in the injured brain and discusses potential future anti-inflammatory strategies for head-injured patients, with an emphasis on the putative beneficial combination therapy of synthetic cannabinoids (e.g., dexanabinol) with PPARα agonists (e.g., fenofibrate).

Decrease in plasma adiponectin level and increase in adiponectin immunoreactivity in cortex and hippocampus after traumatic brain injury in rats

“…Increased pro-inflammatory cytokines stimulate inflammatory cells, leading to the release of damaging reactive oxygen and nitrogen species, elevating the glutamate levels to excitotoxic levels, impairing the ability of glia to buffer the extracellular potassium concentration, thereby compromising the blood-brain barrier and attracting more inflammatory cells to the brain (12, 17). Among the various pathways involved in the inflammatory responses after TBI, recent attention has been paid to the AMPK and PPARα pathways, which have strong anti-inflammatory properties (1, 15,16,18).…”

“…Furthermore, Venkatesh et al recently reported that the plasma adiponectin levels in critically ill patients, including those with sepsis, burns, and trauma, decreased significantly on days 3 and 7 after injury (21), although they did not describe whether their studies included any patients with TBI. The precise mechanism by which adiponectin mediates these effects remains unclear, but it has been shown that adiponectin can activate the AMPK and PPARα pathways (1, 15,16,18), and it has been shown that adiponectin can exert a potent cerebroprotective function though its antiinflammatory and/or anti-apoptotic actions in both the rat and mouse brain ischemia-reperfusion models (2, 13). We speculate that a high level of adiponectin immunoreactivity in the brain may act to reduce neuronal apoptosis after TBI via an anti-inflammatory and/or anti-apoptotic action as a result of AMPK and PPARα pathway activation.…”

“…Research efforts in recent years have provided increasing evidence that the inflammatory response is largely responsible for the poor outcome of TBI (18). Among the various pathways underlying the inflammatory responses after TBI, recent attention has been paid to the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) pathways because they exert strong antiinflammatory effects (1, 15,16,18).…”

Retinoic Acid Induces Neurogenesis by Activating Both Retinoic Acid Receptors (RARs) and Peroxisome Proliferator-activated Receptor β/δ (PPARβ/δ)

“…PPAR␤/␦ expression peaks at E13.5-15.5 days and then decreases slightly but remains high through development and adult life (18,19). It was reported that activation of PPAR␤/␦ induces oligodendrocyte differentiation and enhances neuronal maturation in cultured cell models of neurogenesis (20,21) and that, by exerting anti-apoptotic and anti-inflammatory functions, PPAR␤/␦ displays neuroprotective activities (22). Available information thus raises the possibility that both RAR and PPAR␤/␦ are involved in mediating RA-induced neuronal differentiation.…”

Pharmacology of Traumatic Brain Injury: Where Is the “Golden Bullet”?

“…Promising new findings have been made in molecular mechanisms of TBI, and many experimental substances await testing in the clinical setting. For example, peroxisome proliferator-activated receptors have recently emerged as potent antiinflammatory transcription factors that when used alone or in combination with endocannabinoids may prove to be pivotal antiinflammatory and neuroprotective agents in the setting of TBI (124,125). In addition, selective targeting of the innate immune response after trauma, such as by pharmacological inhibition of the complement cascade at various levels of its activation pathways, has recently emerged as a new promising therapeutic strategy in experimental TBI models (126)(127)(128)(129).…”