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NEUROSURGICAL ANESTHESIA

Sigma Receptor Agonists Provide Neuroprotection In Vitro by Preserving bcl-2

Sufang Yang, MD^*, Anish Bhardwaj, MD, Jian Cheng, PhD^*, Nabil J. Alkayed, MD, PhD^*, Patricia D. Hurn, PhD^*, and Jeffrey R. Kirsch, MD^*

From the Department of *Anesthesiology and Peri-operative Medicine, Oregon Health and Science University, Portland, Oregon; Department of Neurology; and Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Address correspondence to Jeffrey R. Kirsch, MD, Department of Anesthesiology and Peri-operative Medicine, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, UHS-2, Portland, OR 97239-3098. Address e-mail to kirschje{at}ohsu.edu.

BACKGROUND: Sigma ()-receptor agonists attenuate brain injury after experimental focal cerebral ischemia in several species. We tested the hypothesis that the potent, prototypical ₁-receptor agonist, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), protects neurons by a mechanism involving the antiapoptotic protein bcl-2.

METHODS: Primary cortical neuronal cultures were exposed to either 2 h of oxygen–glucose deprivation (OGD) or glutamate (100 µM). PPBP treatment was initiated either 15 min prior to the insult or at 15 min postinsult then continued for 24 h. In another set of experiments, cultured neurons were preincubated for 2 h prior to PPBP treatment with ₁-receptor antagonist, rimcazole, in a dose-dependent manner. Alive and dead cells were detected with calcein-AM and propidium iodide respectively. Bcl-2 and bax expression were determined by quantitative real time reverse transcription polymerase chain reaction and western blotting, and DNA damage was detected by TUNEL staining.

RESULTS: PPBP pretreatment attenuated neuronal injury induced by OGD or glutamate (50 or 100 µM). This protection was reversed with rimcazole (cell death: OGD 48 ± 2%, OGD plus PPBP 31 ± 3%, OGD plus PPBP with rimcazole 46 ± 2%). PPBP treatment increased bcl-2 but not bax mRNA levels. PPBP's ability to preserve bcl-2 protein after OGD by PPBP was fully abolished by rimcazole. Lastly, PPBP reduced the number of TUNEL-positive cells after OGD, suggesting fewer cells with overt DNA damage.

CONCLUSIONS: These data demonstrate that PPBP reduces cell death in vitro by a mechanism involving receptor-dependent preservation of protective genes such as bcl-2

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999