Although radiosurgery has been used widely to treat primary brain tumor and brain metastases, its biological effect on the surrounding normal tissues is unclear. Damage from localized irradiation in different regions of brain may not be restricted to just these areas, but could eventually spread to other regions of the brain producing more diffuse brain injury. Understanding the process and mechanism(s) associated with the spread of normal tissue damage from localized brain irradiation is critical for the development of interventions aimed at preventing or ameliorating the long term effects of radiation-induced brain injury. Our study will provide preclinical data to help clinicians estimate the risk/benefit ratio of using radiosurgery and institute more effective ways of treating brain tumor patients with radiosurgery.

Stem cell loss and reduced neurogenesis in the hippocampus may play an important role in the development of radiation-induced late brain injury, specially, cognitive impairment. We hypothesize that transplantation of neuronal stem cells or GDNF-engineered neuronal stem cells will mitigate radiation-induced decline in neurogenesis by restoring the progressive cell lose and providing neuronal trophic factors to support endogenous cell survival. Currently, we are testing the effect of irradiated microenvironment on the migration and differentiation of neuronal stem cells in vitro and in vivo.

Several lines of evidence suggest a pathogenic link between the nAChR-α7 and brain disordersincluding schizophrenia, Alzheimer’s disease, and traumaticbrain injury. Activation of nAChR-α7can improve cognitive performance in rats, rabbits, and monkeys, whereas blockade ofthose receptors impairs performance. We are using molecular and cellular techniques and rodent model to exploit whether activation of nAChR-α7 will ameliorate the development and progression of radiation-induced brain injury, including inflammation and cognitive dysfunction.

Ramanan S, Zhao W, Riddle DR, Robbins ME. Role of PPARs in radiation-induced brain injury. PPAR Res. 2010; 2010():art.234975.

Robbins ME, Zhao W, Garcia-Espinosa MA Diz DI. Renin-angiotensin system blockers and modulation of radiation-induced brain injury. Curr Drug Targets. 2010; 11(11):1413-1422.

Zhao W, Toler SM, Lippiello PM, Bencherif M. A7 nicotinic receptor agonist enhances neurogenesis and reduces brain inflammation after lipopolysaccharide (LPS) or radiation treatment [abstract]. Eur Neuropsychopharmacol. 2010; 20(Suppl 3):S242.

Robbins ME, Payne V, Tommasi E, Diz DI, Hsu F-C, Brown WR, Wheeler KT, Olson J, Zhao W. The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys. 2009; 73(2):499-505.

Zhao W, Robbins ME. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem. 2009; 16(2):130-143.

Ramanan S, Kooshki M, Zhao W, Hsu F-C, Riddle DR, Robbins ME. The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation. Int J Radiat Oncol Biol Phys. 2009; 75(3):870-877.

Collins-Underwood JR, Zhao W, Sharpe JG, Robbins ME. NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cells. Free Radic Biol Med. 2008; 45(6):929-938.

Smith-Pearson PS, Kooshki M, Spitz DR, Poole LB, Zhao W, Robbins ME. Decreasing peroxiredoxin II expression decreases glutathione, alters cell cycle distribution, and sensitizes glioma cells to ionizing radiation and H2O2. Free Radic Biol Med. 2008; 45(8):1178-1189.

Ramanan S, Kooshki M, Zhao W, Hsu F-C, Robbins ME. PPARalpha ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-kappaB and AP-1 pathways. Free Radic Biol Med. 2008; 45(12):1695-1704.

Robbins M, Payne V, Diz D, Hsu FC, Zhao WL. Chronic inhibition of the renin-angiotensin system prevents radiation-induced cognitive impairment in the adult male rat [abstract]. Neuro Oncol. 2008; 10(5):851.

Zhao W, Payne V, Tommasi E, Diz DI, Hsu F-C, Robbins ME. Administration of the peroxisomal proliferator-activated receptor gamma agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys. 2007; 67(1):6-9.

Smith PS, Zhao W, Spitz DR, Robbins ME. Inhibiting catalase activity sensitizes 36B10 rat glioma cells to oxidative stress. Free Radic Biol Med. 2007; 42(6):787-797.

Zhao W, Iskandar S, Kooshki M, Sharpe JG, Payne V, Robbins ME. Knocking out peroxisome proliferator-activated receptor (PPAR) alpha inhibits radiation-induced apoptosis in the mouse kidney through activation of NF-kappaB and increased expression of IAPs. Radiat Res. 2007; 167(5):581-591.

Zhao W, Diz DI, Robbins ME. Oxidative damage pathways in relation to normal tissue injury. Br J Radiol. 2007; 80(Special Issue 1):S23-S31.

Atwood T, Payne VS, Zhao W, Brown WR, Wheeler KT, Zhu J-M, Robbins ME. Quantitative magnetic resonance spectroscopy reveals a potential relationship between radiation-induced changes in rat brain metabolites and cognitive impairment. Radiat Res. 2007; 168(5):574-581.

Zhao W, Kridel S, Thorburn A, Kooshki M, Little J, Hebbar S, Robbins M. Fatty acid synthase: a novel target for antiglioma therapy. Br J Cancer. 2006; 95(7):869-878.

Collins-Underwood JR, Zhao W, Kooshki M, Robbins M. Role of NADPH oxidase in radiation-induced oxidative stress and inflammation in brain endothelium [abstract]. Free Radic Res. 2006; 40(Suppl 1):S52.

Smith PS, Zhao W, Robbins M. Knocking down catalase increases sensitivity of gliomas to oxidative stress [abstract]. Free Radic Res. 2006; 40(Suppl 1):S70.

Cognition/learning, drugs/therapeutic agents pharm, immunology/allergy/inflammatio, prevention.