Progressive cognitive impairment occurs in up to 50% of primary and metastatic brain tumor patients who survive 6 months or longer after treatment with partial or whole-brain irradiation (WBI);~200,000 patients/year receive these treatments. A growing body of evidence suggests that oxidative stress and pro-inflammatory responses play a critical role in radiation-induced brain injury. These observations provide the rationale for investigating anti-inflammatory-based therapeutic approaches to ameliorate or prevent radiation-induced brain injury. This competitive renewal will focus on the role of the peroxisomal proliferator-activated receptors 1 and 4 (PPAR1, PPAR4) in ameliorating or preventing radiation-induced brain injury, including cognitive impairment. These PPARs are potent mediators of anti-inflammatory responses. During the current funding period, we have demonstrated that i) administration of the PPAR3 agonist, pioglitazone, prevents fractionated WBI- induced cognitive impairment in young adult male rats;ii) the irradiated brains of PPAR1 KO mice have increased microglial activation, iii] administration of the PPAR1 agonist, fenofibrate, prevents both WBI-induced microglial activation and decreased neurogenesis, and iii) pre-treatment of microglial cells with PPAR1 agonists prevents radiation-induced increases in inflammation. In this competitive renewal, we propose to extend our PPAR1 studies and initiate studies on PPAR4, increasingly recognized as a promising pharmacological target for neuroprotection. We hypothesize that administration of PPAR1 and/or PPAR4 agonists will not only ameliorate or prevent radiation-induced brain injury, including cognitive impairment, but will also inhibit brain tumor growth. To test this hypothesis, we will pursue the following Specific Aims: 1] using a fractionated WBI rat model, we will determine if administration of PPAR1 or PPAR4 agonists will ameliorate or prevent radiation-induced brain injury, including cognitive impairment;2] using PPAR4 KO mice, we will determine if i] knocking down PPAR4 will increase radiation-induced brain injury, and ii] if administering a PPAR4 agonist will ameliorate or prevent radiation-induced brain injury through PPAR4- dependent mechanisms;3] using murine hippocampal neurons and microglial cells, we will determine if incubating these cells with PPAR4 agonists modulates radiation-induced changes in cellular phenotype via inhibition of pro-inflammatory signaling pathways and/or upregulation of anti-inflammatory mediators;and 4] using human glioma cell lines and immortalized normal glial cells, we will determine if treating with PPAR1 or PPAR4 agonists leads to selective glioma cell kill. Further, we will use an in vivo orthotopic rat model to determine if administering PPAR1 or PPAR4 agonists, alone or in combination with ionizing radiation, inhibits tumor growth and increases survival times. Successful completion of these aims will serve as the foundation for translating these findings into clinical trials designed to enhance the quality of life and long-term survival of cancer patients receiving partial or WBI.
Approximately 100,000 cancer patients per year survive long enough after partial or WBI to develop radiation- induced injury, including cognitive impairment. No successful long-term treatments for radiation-induced brain injury are currently available nor are there any effective preventive strategies. The establishment of an interventional role for PPAR1 and/or PPAR4 in radiation-induced brain injury should lead to the rapid translation of these preclinical findings to the clinic, thereby, increasing the therapeutic window for cancer patients receiving partial or WBI as well as impacting both on their quality of life and their long-term survival.
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