Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases

Tauheed Ishrat, Iqbal Sayeed, Fahim Atif, Fang Hua, Donald G. Stein

Research output: Contribution to journalArticle

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Abstract

Blood-brain barrier (BBB) breakdown after stroke is linked to the up-regulation of metalloproteinases (MMPs) and inflammation. This study examines the effects of progesterone (PROG) and its neuroactive metabolite allopregnanolone (ALLO) on BBB integrity following permanent middle cerebral artery occlusion (pMCAO). Rats underwent pMCAO by electro-coagulation and received intraperitoneal injections of PROG (8. mg/kg), ALLO (8. mg/kg) or vehicle at 1. h post-occlusion and then subcutaneous injections (8. mg/kg) at 6, 24, and 48. h. MMP activation and expression were analyzed by Western blot, immunohistochemistry and gelatin zymography 72. h post-pMCAO. Occludin1, claudin5, tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) were analyzed at 72. h post-pMCAO with Western blots. BBB permeability was measured by Evans blue extravasation and infarct size was evaluated by cresyl violet at 72. h after pMCAO. Ischemic injury significantly (p< 0.05) increased the expression of MMP-9, MMP-2, TNF-α and IL-6, and reduced the levels of occludin1 and claudin5. These changes were followed by increased infarct size (% contralateral hemisphere) and Evans blue extravasation into the brain indicating compromise of the BBB. PROG and ALLO attenuated BBB disruption and infarct size following pMCAO by reducing MMPs and the inflammatory response and by preventing the degradation of occludin1 and claudin5. We conclude that PROG and ALLO can help to protect BBB disruption following pMCAO.

Original languageEnglish (US)
Pages (from-to)183-190
Number of pages8
JournalExperimental Neurology
Volume226
Issue number1
DOIs
StatePublished - Nov 1 2010

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Pregnanolone
Middle Cerebral Artery Infarction
Blood-Brain Barrier
Matrix Metalloproteinases
Progesterone
Ischemia
Evans Blue
Interleukin-6
Tumor Necrosis Factor-alpha
Western Blotting
Metalloproteases
Subcutaneous Injections
Gelatin
Intraperitoneal Injections
Permeability
Up-Regulation
Immunohistochemistry
Stroke
Inflammation
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience
  • Medicine(all)

Cite this

Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases. / Ishrat, Tauheed; Sayeed, Iqbal; Atif, Fahim; Hua, Fang; Stein, Donald G.

In: Experimental Neurology, Vol. 226, No. 1, 01.11.2010, p. 183-190.

Research output: Contribution to journalArticle

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