Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke

Zhenjun Tan, Ryan C. Turner, Rachel L. Leon, Xinlan Li, Jarin Hongpaisan, Wen Zheng, Aric F. Logsdon, Zachary J. Naser, Daniel L. Alkon, Charles L. Rosen, Jason D. Huber

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE - Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator reperfusion in aged rats. METHODS - Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18- to 20-month-old female Sprague-Dawley rats using an autologous blood clot with tissue plasminogen activator-mediated reperfusion. Bryostatin was administered at 6 hours post-MCAO, then at 3, 6, 9, 12, 15, and 18 days after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 days after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 days post-MCAO. Histological assessment of PKC isozymes was performed at 24 hours post-MCAO. RESULTS - Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 days. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 days post-MCAO. Changes in αPKC expression and εPKC expression in neurons were noted in bryostatin-treated rats at 24 hours post-MCAO. CONCLUSIONS - Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome after MCAO.

Original languageEnglish (US)
Pages (from-to)3490-3497
Number of pages8
JournalStroke
Volume44
Issue number12
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

Fingerprint

Bryostatins
Brain Injuries
Stroke
Protein Kinase C
Tissue Plasminogen Activator
Brain Ischemia
Reperfusion
Atrophy
Middle Cerebral Artery Infarction
Isoenzymes
Sprague Dawley Rats
Alzheimer Disease
Thrombosis
Necrosis
Ischemia
Neurons

Keywords

  • Aging
  • Blood-brain barrier
  • Infarction
  • Protein kinase C
  • Tissue plasminogen activator

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Cite this

Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke. / Tan, Zhenjun; Turner, Ryan C.; Leon, Rachel L.; Li, Xinlan; Hongpaisan, Jarin; Zheng, Wen; Logsdon, Aric F.; Naser, Zachary J.; Alkon, Daniel L.; Rosen, Charles L.; Huber, Jason D.

In: Stroke, Vol. 44, No. 12, 01.12.2013, p. 3490-3497.

Research output: Contribution to journalArticle

Tan, Z, Turner, RC, Leon, RL, Li, X, Hongpaisan, J, Zheng, W, Logsdon, AF, Naser, ZJ, Alkon, DL, Rosen, CL & Huber, JD 2013, 'Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke', Stroke, vol. 44, no. 12, pp. 3490-3497. https://doi.org/10.1161/STROKEAHA.113.002411
Tan, Zhenjun ; Turner, Ryan C. ; Leon, Rachel L. ; Li, Xinlan ; Hongpaisan, Jarin ; Zheng, Wen ; Logsdon, Aric F. ; Naser, Zachary J. ; Alkon, Daniel L. ; Rosen, Charles L. ; Huber, Jason D. / Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke. In: Stroke. 2013 ; Vol. 44, No. 12. pp. 3490-3497.
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T1 - Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke

AU - Tan, Zhenjun

AU - Turner, Ryan C.

AU - Leon, Rachel L.

AU - Li, Xinlan

AU - Hongpaisan, Jarin

AU - Zheng, Wen

AU - Logsdon, Aric F.

AU - Naser, Zachary J.

AU - Alkon, Daniel L.

AU - Rosen, Charles L.

AU - Huber, Jason D.

PY - 2013/12/1

Y1 - 2013/12/1

N2 - BACKGROUND AND PURPOSE - Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator reperfusion in aged rats. METHODS - Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18- to 20-month-old female Sprague-Dawley rats using an autologous blood clot with tissue plasminogen activator-mediated reperfusion. Bryostatin was administered at 6 hours post-MCAO, then at 3, 6, 9, 12, 15, and 18 days after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 days after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 days post-MCAO. Histological assessment of PKC isozymes was performed at 24 hours post-MCAO. RESULTS - Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 days. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 days post-MCAO. Changes in αPKC expression and εPKC expression in neurons were noted in bryostatin-treated rats at 24 hours post-MCAO. CONCLUSIONS - Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome after MCAO.

AB - BACKGROUND AND PURPOSE - Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator reperfusion in aged rats. METHODS - Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18- to 20-month-old female Sprague-Dawley rats using an autologous blood clot with tissue plasminogen activator-mediated reperfusion. Bryostatin was administered at 6 hours post-MCAO, then at 3, 6, 9, 12, 15, and 18 days after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 days after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 days post-MCAO. Histological assessment of PKC isozymes was performed at 24 hours post-MCAO. RESULTS - Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 days. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 days post-MCAO. Changes in αPKC expression and εPKC expression in neurons were noted in bryostatin-treated rats at 24 hours post-MCAO. CONCLUSIONS - Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome after MCAO.

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KW - Blood-brain barrier

KW - Infarction

KW - Protein kinase C

KW - Tissue plasminogen activator

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