Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury

Following traumatic brain injury (TBI) there is significant neuropathology which includes mitochondrial dysfunction, loss of cortical gray matter, microglial activation, and cognitive impairment. Previous evidence has shown that activation of the peroxisome proliferator-activated receptors (PPARs) provide neuroprotection following traumatic brain and spinal injuries. In the current study we hypothesized that treatment with the PPAR ligand Pioglitazone would promote neuroprotection following a rat controlled cortical impact model of TBI. Animals received a unilateral 1.5 mm controlled cortical impact followed by administration of Pioglitazone at 10 mg/kg beginning 15 min after the injury and subsequently every 24 h for 5 days. Beginning 1 day after the injury there was significant impairment in mitochondrial bioenergetic function which was attenuated by treatments with Pioglitazone at 15 min and 24 h (p < 0.05). In an additional set of animals, cognitive function was assessed using the Morris Water Maze (MWM) and it was observed that over the course of 4 days of testing the injury produced a significant increase in both latency (p < 0.05) and distance (p < 0.05) to the platform. Animals treated with Pioglitazone performed similarly to sham animals and did not exhibit any impairment in MWM performance. Sixteen days after the injury tissue sections through the lesion site were quantified to determine the size of the cortical lesion. Vehicle-treated animals had an average lesion size of 5.09 ± 0.73 mm3 and treatment with Pioglitazone significantly reduced the lesion size by 55% to 2.27 ± 0.27 mm3 (p < 0.01). Co-administration of the antagonist T0070907 with Pioglitazone blocked the protective effect seen with administration of Pioglitazone by itself. Following the injury there was a significant increase in the number of activated microglia in the area of the cortex adjacent to the site of the lesion (p < 0.05). Treatment with Pioglitazone prevented the increase in the number of activated microglia and no difference was observed between sham and Pioglitazone-treated animals. From these studies we conclude that following TBI Pioglitazone is capable ameliorating multiple aspects of neuropathology. These studies provide further support for the use of PPAR ligands, specifically Pioglitazone, for neuroprotection.

Research Highlights►Pioglitazone attenuates mitochondrial dysfunction following TBI. ►Pioglitazone attenuates cognitive dysfunction via a PPARγ mediated pathway. ►Pioglitazone attenuates cortical tissue loss via a PPARγ mediated pathway. ►Pioglitazone attenuates microglial activation via a PPARγ independent pathway.