Ischemic neuroprotection with selective κ-opioid receptor agonist is gender specific

Chih Hung Chen, Thomas J K Toung, Patricia D. Hum, Raymond C. Koehler, Anish Bhardwaj

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background and Purpose - We demonstrated previously that treatment with selective κ-opioid receptor (KOR) agonist BRL 52537 hydrochloride [(±)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine] (1) has a long therapeutic window for providing ischemic neuroprotection, and (2) attenuates ischemia-evoked NO production in vivo in rats. Neuronally derived NO has been shown to be deleterious in the male but not in the female rodent model of focal ischemic stroke. We tested the hypothesis that BRL provides significant neuroprotection from transient focal ischemia in male but not in female rats. Methods - Halothane-anesthetized adult male and female Wistar rats (250 to 275 g) were subjected to 2 hours of middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. In the first experiment, male and female rats were treated in a blinded randomized fashion with vehicle saline or 1 mg/kg per hour BRL infusion started at the onset of reperfusion and continued for 22 hours. In the second experiment, ovariectomized (OVX) female rats were treated with vehicle or BRL. Infarct volume in the cortex and caudoputamen (CP) complex was assessed by triphenyl tetrazolium chloride staining at 72 hours after MCAO. Results - Infarct volume (percentage of ipsilateral structure; mean±SEM) was attenuated significantly in male rats with BRL treatment (cortex 23±5%; CP 44±6%; n=15) compared with vehicle-treated male rats (cortex 38±4%; CP 66±4%; n=15) but not in female rats (BRL-cortex 26±6; CP 55±8%; vehicle-cortex 26±5; CP 62±5%; n = 10 each). Neurologic deficit score was improved in BRL-treated male rats but not in female rats. Infarct volume was not different in OVX female rats treated with vehicle or BRL. Conclusions - These data: (1) demonstrate that this dose of selective KOR agonist provides ischemic neuroprotection in male but not female rats, (2) demonstrate that the lack of protection by BRL is not attributable to circulating ovarian hormones, and (3) highlight the importance of using animal models of both sexes in preclinical studies of experimental ischemia.

Original languageEnglish (US)
Pages (from-to)1557-1561
Number of pages5
JournalStroke
Volume36
Issue number7
DOIs
StatePublished - Jul 2005
Externally publishedYes

Fingerprint

Opioid Receptors
Middle Cerebral Artery Infarction
Ischemia
Reperfusion
Neuroprotection
Suture Techniques
Parietal Lobe
Laser-Doppler Flowmetry
Halothane
Neurologic Manifestations
Wistar Rats
Chlorides
Rodentia
Animal Models
Stroke
Hormones
Staining and Labeling

Keywords

  • Cerebral ischemia, focal
  • Gender
  • Neuroprotection
  • Receptors, opioid
  • Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Cite this

Ischemic neuroprotection with selective κ-opioid receptor agonist is gender specific. / Chen, Chih Hung; Toung, Thomas J K; Hum, Patricia D.; Koehler, Raymond C.; Bhardwaj, Anish.

In: Stroke, Vol. 36, No. 7, 07.2005, p. 1557-1561.

Research output: Contribution to journalArticle

Chen, Chih Hung ; Toung, Thomas J K ; Hum, Patricia D. ; Koehler, Raymond C. ; Bhardwaj, Anish. / Ischemic neuroprotection with selective κ-opioid receptor agonist is gender specific. In: Stroke. 2005 ; Vol. 36, No. 7. pp. 1557-1561.
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abstract = "Background and Purpose - We demonstrated previously that treatment with selective κ-opioid receptor (KOR) agonist BRL 52537 hydrochloride [(±)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine] (1) has a long therapeutic window for providing ischemic neuroprotection, and (2) attenuates ischemia-evoked NO production in vivo in rats. Neuronally derived NO has been shown to be deleterious in the male but not in the female rodent model of focal ischemic stroke. We tested the hypothesis that BRL provides significant neuroprotection from transient focal ischemia in male but not in female rats. Methods - Halothane-anesthetized adult male and female Wistar rats (250 to 275 g) were subjected to 2 hours of middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. In the first experiment, male and female rats were treated in a blinded randomized fashion with vehicle saline or 1 mg/kg per hour BRL infusion started at the onset of reperfusion and continued for 22 hours. In the second experiment, ovariectomized (OVX) female rats were treated with vehicle or BRL. Infarct volume in the cortex and caudoputamen (CP) complex was assessed by triphenyl tetrazolium chloride staining at 72 hours after MCAO. Results - Infarct volume (percentage of ipsilateral structure; mean±SEM) was attenuated significantly in male rats with BRL treatment (cortex 23±5{\%}; CP 44±6{\%}; n=15) compared with vehicle-treated male rats (cortex 38±4{\%}; CP 66±4{\%}; n=15) but not in female rats (BRL-cortex 26±6; CP 55±8{\%}; vehicle-cortex 26±5; CP 62±5{\%}; n = 10 each). Neurologic deficit score was improved in BRL-treated male rats but not in female rats. Infarct volume was not different in OVX female rats treated with vehicle or BRL. Conclusions - These data: (1) demonstrate that this dose of selective KOR agonist provides ischemic neuroprotection in male but not female rats, (2) demonstrate that the lack of protection by BRL is not attributable to circulating ovarian hormones, and (3) highlight the importance of using animal models of both sexes in preclinical studies of experimental ischemia.",
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AU - Bhardwaj, Anish

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N2 - Background and Purpose - We demonstrated previously that treatment with selective κ-opioid receptor (KOR) agonist BRL 52537 hydrochloride [(±)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine] (1) has a long therapeutic window for providing ischemic neuroprotection, and (2) attenuates ischemia-evoked NO production in vivo in rats. Neuronally derived NO has been shown to be deleterious in the male but not in the female rodent model of focal ischemic stroke. We tested the hypothesis that BRL provides significant neuroprotection from transient focal ischemia in male but not in female rats. Methods - Halothane-anesthetized adult male and female Wistar rats (250 to 275 g) were subjected to 2 hours of middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. In the first experiment, male and female rats were treated in a blinded randomized fashion with vehicle saline or 1 mg/kg per hour BRL infusion started at the onset of reperfusion and continued for 22 hours. In the second experiment, ovariectomized (OVX) female rats were treated with vehicle or BRL. Infarct volume in the cortex and caudoputamen (CP) complex was assessed by triphenyl tetrazolium chloride staining at 72 hours after MCAO. Results - Infarct volume (percentage of ipsilateral structure; mean±SEM) was attenuated significantly in male rats with BRL treatment (cortex 23±5%; CP 44±6%; n=15) compared with vehicle-treated male rats (cortex 38±4%; CP 66±4%; n=15) but not in female rats (BRL-cortex 26±6; CP 55±8%; vehicle-cortex 26±5; CP 62±5%; n = 10 each). Neurologic deficit score was improved in BRL-treated male rats but not in female rats. Infarct volume was not different in OVX female rats treated with vehicle or BRL. Conclusions - These data: (1) demonstrate that this dose of selective KOR agonist provides ischemic neuroprotection in male but not female rats, (2) demonstrate that the lack of protection by BRL is not attributable to circulating ovarian hormones, and (3) highlight the importance of using animal models of both sexes in preclinical studies of experimental ischemia.

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