Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury - PubMed (original) (raw)

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

Andrew Sauerbeck et al. Exp Neurol. 2011 Jan.

Abstract

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 1.5mm controlled cortical impact followed by administration of Pioglitazone at 10mg/kg beginning 15min after the injury and subsequently every 24h for 5days. Beginning 1day after the injury there was significant impairment in mitochondrial bioenergetic function which was attenuated by treatments with Pioglitazone at 15min and 24h (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 4days 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±0.73mm(3) and treatment with Pioglitazone significantly reduced the lesion size by 55% to 2.27±0.27mm(3) (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.

2010 Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. Pioglitazone treatment attenuates mitochondrial dysfunction after TBI

In order to assess the ability of Pioglitazone to prevent the mitochondrial dysfunction which occurs with this model of TBI, mitochondrial bioenergetic function was analyzed 1 day following a controlled cortical impact TBI. A. Following a single injection of Pioglitazone (10mg/kg) 15 minutes after the injury, no improvements in mitochondrial function were observed. B. When Pioglitazone was administered at both at 15 minutes and 24 hours after the injury (10mg/kg/injection) a significant increase in mitochondrial bioenergetics was observed. These studies indicate that treatment with Pioglitazone at 15 minutes and 24 hours is capable of preventing mitochondrial dysfunction following TBI. (* p<0.01 by one-way ANOVA with SNK post-test).

Figure 2

Figure 2. Pioglitazone treatment reduces cognitive impairment following traumatic brain injury

With this model of TBI there are impairments in Morris Water Maze (MWM) performance following the injury. Pioglitazone was administered for 5 days following the injury in order to determine if treatment with Pioglitazone is capable of preventing cognitive impairment with the MWM test. Treatment with Pioglitazone produced a significant reduction in both the distance and latency to find the platform following TBI. Additionally, animals which were also treated with the PPARγ antagonist T0070907 exhibited no preservation of function indicating that PPARγ receptor activation is required for Pioglitazone's ability to preserve cognitive functioning. (* p<0.05 by one-way ANOVA).

Figure 3

Figure 3. Pioglitazone treatment reduces cortical tissue loss

Following a cortical impact brain injury there is significant loss of cortical tissue which occurs in the days and weeks following the injury, Pioglitazone was administered for 5 days following a unilateral cortical contusion in order to access the ability of Pioglitazone to reduce cortical damage. In these studies Pioglitazone treatment reduced the size of the lesion which occurs in this CCI rat model of TBI. These studies also indicate that activation of the PPARγ receptor is required for this aspect of Pioglitazone's neuroprotective function since treatment with the PPARγ antagonist blocked the therapeutic effect. A. Representative coronal sections stained with neutral red for animals treated with vehicle, Pioglitazone, Pioglitazone and T0070907, or T0070907 alone at 16 days post-injury. Scale bar=1000 μm B. Lesion volume quantification showed a significantly reduced lesion volume in Pioglitazone-treated CCI animals when compared with the vehicle group and antagonist treatment prevented this effect (*=p<0.05, one-way ANOVA with SNK post-test).

Figure 4

Figure 4. Pioglitazone reduces post-injury microglial activation following TBI

With this cortical contusion model of TBI there is significant inflammation which occurs following the injury. Pioglitazone was administered for 5 days following the injury in order to assess its ability to reduce inflammation following TBI. In this model, Pioglitazone attenuated the neuroinflammatory response in the injured animals. These studies also show that Pioglitazone does not require the PPARγ receptor in order to reduce inflammation following injury since treatment with the PPARγ inhibitor T0070907 did not block Pioglitazone's neuroprotective effects. A. Immunohistochemistry for OX-42 was shown in cerebral cortex adjacent to the cortical lesion. The bottom images are high magnification views of the boxed regions. Scale bar = 100μm. B. Total number of activated microglia was counted in the cortex and a reduction in the number of activated microglia was found in Pioglitazone treated animals compared to vehicle treated animals. Compared with sham animals, Pioglitazone treated animals exhibited no significant increase in activated microglia. (* p<0.05 by one-way ANOVA with SNK post-test).

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