Phenoxybenzamine is neuroprotective in a rat model of severe traumatic brain injury.
Phenoxybenzamine (PBZ) is an FDA approved α-1 adrenergic receptor antagonist that is currently used to treat symptoms of pheochromocytoma. However, it has not been studied as a neuroprotective agent for traumatic brain injury (TBI). While screening neuroprotective candidates, we found that phenoxybenzamine reduced neuronal death in rat hippocampal slice cultures following exposure to oxygen glucose deprivation (OGD). Using this system, we found that phenoxybenzamine reduced neuronal death over a broad dose range (0.1 µM-1 mM) and provided efficacy when delivered up to 16 h post-OGD. We further tested phenoxybenzamine in the rat lateral fluid percussion model of TBI. When administered 8 h after TBI, phenoxybenzamine improved neurological severity scoring and foot fault assessments. At 25 days post injury, phenoxybenzamine treated TBI animals also showed a significant improvement in both learning and memory compared to saline treated controls. We further examined gene expression changes within the cortex following TBI. At 32 h post-TBI phenoxybenzamine treated animals had significantly lower expression of pro-inflammatory signaling proteins CCL2, IL1β, and MyD88, suggesting that phenoxybenzamine may exert a neuroprotective effect by reducing neuroinflammation after TBI. These data suggest that phenonxybenzamine may have application in the treatment of TBI.
Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA. Thomas.Rau@mso.umt.edu.
Thomas F
TF
Rau
Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA. aakriti_kothiwal@yahoo.com.
Aakriti
A
Kothiwal
Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA. annela.rova@umconnect.umt.edu.
Annela
A
Rova
Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA. fred.rhoderick@mso.umt.edu.
Joseph F
JF
Rhoderick
Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA. david.poulsen@umontana.edu.
David J
DJ
Poulsen
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy*; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D018782:Maze Learning; D008568:Memory; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010643:Phenoxybenzamine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D053583:Interleukin-1beta; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D018696:Neuroprotective Agents; D010643:Phenoxybenzamine