Neuroendocrine mechanism for tolerance to cerebral ischemia-reperfusion injury in male rats

Shao Hua Yang, Ran Liu, Yi Wen, Evelyn Perez, Jason Cutright, Anne Marie Brun-Zinkernagel, Meharvan Singh, Arthur L. Day, James W. Simpkins

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Testosterone has been shown to exacerbate cerebral ischemia-reperfusion injury, which suggests that the well-known stress-induced testosterone reduction could be a protective response. We hypothesized that stress-induced testosterone reduction contributes to ischemia tolerance in cerebral ischemia-reperfusion injury in male rats. In intact male rats, stress was induced by brief anesthesia at 6 h before transient middle cerebral artery occlusion (MCAO). Testosterone levels were significantly decreased 6 h after stress. Testosterone reduction was associated with a 50% reduction in cerebral lesion volume in the stressed animals. Further, the stress-induced cerebral ischemia tolerance was eliminated by testosterone replacement in castrated males. Immunohistochemical staining showed that androgen receptors were up-regulated after cerebral ischemia-reperfusion injury and partially colocalized with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells in the parietal cortex and extensively colocalized in the caudate putamen. Heat shock protein 70 (Hsp70) and 90 (Hsp90) are involved in ischemia tolerance, and were not colocalized with TUNEL in the immunohistochemical staining, suggesting an anti-apoptotic role of Hsp's. To determine the effect of testosterone on MCAO-induced Hsp70 and -90 expression, a testosterone replacement or withdrawal paradigm was used. Testosterone-replaced animals exhibited a decrease in Hsp expression, whereas testosterone withdrawal (mimicking the stress-induced testosterone suppression) normalized this deficit. In summary, stress-induced testosterone reduction contributes to ischemia tolerance in cerebral ischemia-reperfusion injury in males, which could be related to the loss of inhibition by testosterone of Hsp70 and -90 expression.

Original languageEnglish
Pages (from-to)341-351
Number of pages11
JournalJournal of Neurobiology
Volume62
Issue number3
DOIs
StatePublished - 15 Feb 2005

Fingerprint

Reperfusion Injury
Brain Ischemia
Testosterone
HSP90 Heat-Shock Proteins
HSP70 Heat-Shock Proteins
Ischemia
Middle Cerebral Artery Infarction
Staining and Labeling
Parietal Lobe
DNA Nucleotidylexotransferase
Putamen
Androgen Receptors
Transferases
Anesthesia

Keywords

  • Androgen receptor
  • Cerebral ischemia tolerance
  • Heat shock protein
  • Ischemia-reperfusion injury
  • Neuroendocrine
  • Preconditioning
  • Testosterone

Cite this

Yang, Shao Hua ; Liu, Ran ; Wen, Yi ; Perez, Evelyn ; Cutright, Jason ; Brun-Zinkernagel, Anne Marie ; Singh, Meharvan ; Day, Arthur L. ; Simpkins, James W. / Neuroendocrine mechanism for tolerance to cerebral ischemia-reperfusion injury in male rats. In: Journal of Neurobiology. 2005 ; Vol. 62, No. 3. pp. 341-351.
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abstract = "Testosterone has been shown to exacerbate cerebral ischemia-reperfusion injury, which suggests that the well-known stress-induced testosterone reduction could be a protective response. We hypothesized that stress-induced testosterone reduction contributes to ischemia tolerance in cerebral ischemia-reperfusion injury in male rats. In intact male rats, stress was induced by brief anesthesia at 6 h before transient middle cerebral artery occlusion (MCAO). Testosterone levels were significantly decreased 6 h after stress. Testosterone reduction was associated with a 50{\%} reduction in cerebral lesion volume in the stressed animals. Further, the stress-induced cerebral ischemia tolerance was eliminated by testosterone replacement in castrated males. Immunohistochemical staining showed that androgen receptors were up-regulated after cerebral ischemia-reperfusion injury and partially colocalized with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells in the parietal cortex and extensively colocalized in the caudate putamen. Heat shock protein 70 (Hsp70) and 90 (Hsp90) are involved in ischemia tolerance, and were not colocalized with TUNEL in the immunohistochemical staining, suggesting an anti-apoptotic role of Hsp's. To determine the effect of testosterone on MCAO-induced Hsp70 and -90 expression, a testosterone replacement or withdrawal paradigm was used. Testosterone-replaced animals exhibited a decrease in Hsp expression, whereas testosterone withdrawal (mimicking the stress-induced testosterone suppression) normalized this deficit. In summary, stress-induced testosterone reduction contributes to ischemia tolerance in cerebral ischemia-reperfusion injury in males, which could be related to the loss of inhibition by testosterone of Hsp70 and -90 expression.",
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Yang, SH, Liu, R, Wen, Y, Perez, E, Cutright, J, Brun-Zinkernagel, AM, Singh, M, Day, AL & Simpkins, JW 2005, 'Neuroendocrine mechanism for tolerance to cerebral ischemia-reperfusion injury in male rats', Journal of Neurobiology, vol. 62, no. 3, pp. 341-351. https://doi.org/10.1002/neu.20103

Neuroendocrine mechanism for tolerance to cerebral ischemia-reperfusion injury in male rats. / Yang, Shao Hua; Liu, Ran; Wen, Yi; Perez, Evelyn; Cutright, Jason; Brun-Zinkernagel, Anne Marie; Singh, Meharvan; Day, Arthur L.; Simpkins, James W.

In: Journal of Neurobiology, Vol. 62, No. 3, 15.02.2005, p. 341-351.

Research output: Contribution to journalArticle

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T1 - Neuroendocrine mechanism for tolerance to cerebral ischemia-reperfusion injury in male rats

AU - Yang, Shao Hua

AU - Liu, Ran

AU - Wen, Yi

AU - Perez, Evelyn

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AU - Brun-Zinkernagel, Anne Marie

AU - Singh, Meharvan

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AB - Testosterone has been shown to exacerbate cerebral ischemia-reperfusion injury, which suggests that the well-known stress-induced testosterone reduction could be a protective response. We hypothesized that stress-induced testosterone reduction contributes to ischemia tolerance in cerebral ischemia-reperfusion injury in male rats. In intact male rats, stress was induced by brief anesthesia at 6 h before transient middle cerebral artery occlusion (MCAO). Testosterone levels were significantly decreased 6 h after stress. Testosterone reduction was associated with a 50% reduction in cerebral lesion volume in the stressed animals. Further, the stress-induced cerebral ischemia tolerance was eliminated by testosterone replacement in castrated males. Immunohistochemical staining showed that androgen receptors were up-regulated after cerebral ischemia-reperfusion injury and partially colocalized with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells in the parietal cortex and extensively colocalized in the caudate putamen. Heat shock protein 70 (Hsp70) and 90 (Hsp90) are involved in ischemia tolerance, and were not colocalized with TUNEL in the immunohistochemical staining, suggesting an anti-apoptotic role of Hsp's. To determine the effect of testosterone on MCAO-induced Hsp70 and -90 expression, a testosterone replacement or withdrawal paradigm was used. Testosterone-replaced animals exhibited a decrease in Hsp expression, whereas testosterone withdrawal (mimicking the stress-induced testosterone suppression) normalized this deficit. In summary, stress-induced testosterone reduction contributes to ischemia tolerance in cerebral ischemia-reperfusion injury in males, which could be related to the loss of inhibition by testosterone of Hsp70 and -90 expression.

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