Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin

doi:10.1016/j.neuroscience.2003.12.029

Neuroscience

Volume 124, Issue 3, 2004, Pages 583-591

https://doi.org/10.1016/j.neuroscience.2003.12.029 Get rights and content

Abstract

There is increasing evidence that physical activity is associated with a decreased stroke risk. The purpose of this study was to determine if exercise could also reduce brain damage in rats subjected to transient middle cerebral artery (MCA) occlusion, and if the reduced brain injury is associated with angiogenesis as well as cellular expression of the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in regions supplied by the MCA.

Adult male Sprague Dawley rats (n=36) exercised 30 min each day for 3 weeks on a treadmill on which repetitive locomotor movement was required. Then, stroke was induced by a 2-h MCA occlusion using an intraluminal filament, followed by 48 h of reperfusion. In addition to the two exercised groups of animals with or without MCA occlusion, there were two other groups of animals, with or without MCA occlusion, housed for the same duration and used as non-exercised controls. Brain damage in ischemic rats was evaluated by neurologic deficits and infarct volume. Exercise preconditioned and non-exercised brains were processed for immunocytochemistry to quantify the number of microvessels or NGF- and BDNF-labeled cells.

Pre-ischemic motor activity significantly (P<0.01) reduced neurologic deficits and infarct volume in the frontoparietal cortex and dorsolateral striatum. Cellular expressions of NGF and BDNF were significantly (P<0.01) increased in cortex (neuron) and striatum (glia) of rats under the exercise condition. Significant (P<0.01) increases in microvessel density were found in striatum.

Physical activity reduced stroke damage. The reduced brain damage may be attributable to angiogenesis and neurotrophin overexpression in brain regions supplied by the MCA following exercise.

Section snippets

Subjects

Adult male Sprague–Dawley rats (260–300 g; Charles River, Wilmington, MA, USA) were housed in the same animal care facility during a 12-h light/dark cycle throughout the protocol. Animal care and surgical procedures were carried out in accordance with guidelines approved by the NIH and Wayne State University Animal Investigation Committee on the ethical use of animals.international guidelines on the ethical use of animals.> All efforts were made to minimize the suffering and the number of

Neurological examination

Neurologic deficits during ischemia and after the onset of reperfusion were compared between ischemic rats with or without prior motor exercise (Fig. 1). ANOVA analysis revealed a significant difference [F_(1,16)=17.5, P<0.01] between exercised and non-exercised groups. Duncan's multiple range test further indicated that exercised rats (M=1.825) had many fewer neurologic deficits compared with non-exercised rats (M=3.125). Since a significant difference was found among the times after repeated

Discussion

In rats preconditioned by treadmill exercise for 3 weeks prior to stroke, we demonstrated significant reductions in neurologic deficits and infarct volume. In non-ischemic rats after the same schedule of motor exercise, we demonstrated significant increases in microvessel density and cellular expression of NGF and BDNF in MCA-supplied brain regions including cortex and striatum.

The phenomenon of “warm up” angina has been known for four decades (Maybaum et al., 1996). When patients with coronary

Acknowledgements

We are grateful to Yandong Zhou, BS, MS, for his help in the preparation of this manuscript. Dr. James P. McAllister II is also appreciated for his support and encouragement of this study. This work was supported partially by American Heart Association Midwest Affiliate Grant in Aid and Wayne State University Research Stimulation Fund to Yuchuan Ding.

References (67)

E.T. Ang et al.
Neuroprotection associated with runningIs it a result of increased endogenous neurotrophic factors?
Neuroscience
(2003)
I. Ay et al.
Intravenous basic fibroblast growth factor (bFGF) decreases DNA fragmentation and prevents downregulation of Bcl-2 expression in the ischemic brain following middle cerebral artery occlusion in rats
Brain Res Mol Brain Res
(2001)
J.E. Black et al.
Capillary and mitochondrial support of neural plasticity in adult rat visual cortex
Exp Neurol
(1991)
Y. Ding et al.
Impaired motor activity and motor learning function in rat with middle cerebral artery occlusion
Behav Brain Res
(2002)
B.R. Ickes et al.
Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain
Exp Neurol
(2000)
N. Jiang et al.
Delayed intravenous administration of basic fibroblast growth factor (bFGF) reduces infarct volume in a model of focal cerebral ischemia/reperfusion in the rat
J Neurol Sci
(1996)
J.A. Kleim et al.
Exercise induces angiogenesis but does not alter movement representations within rat motor cortex
Brain Res
(2002)
S. Maybaum et al.
Improvement in ischemic parameters during repeated exercise testingA possible model for myocardial preconditioning
Am J Cardiol
(1996)
S.A. Neeper et al.
Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain
Brain Res
(1996)
Z. Radak et al.
Exercise preconditioning against hydrogen peroxide-induced oxidative damage in proteins of rat myocardium
Arch Biochem Biophys
(2000)

Z. Radak et al.

Regular training modulates the accumulation of reactive carbonyl derivatives in mitochondrial and cytosolic fractions of rat skeletal muscle

Arch Biochem Biophys

(2000)

J.M. Ren et al.

Time window of infarct reduction by intravenous basic fibroblast growth factor in focal cerebral ischemia

Eur J Pharmacol

(1997)

R.A. Swain et al.

Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat

Neuroscience

(2003)

M. Torasdotter et al.

Environmental enrichment results in higher levels of nerve growth factor mRNA in the rat visual cortex and hippocampus

Behav Brain Res

(1998)

H. Yanamoto et al.

Infarct tolerance against temporary focal ischemia following spreading depression in rat brain

Brain Res

(1998)

H. Yanamoto et al.

Infarct tolerance induced by intra-cerebral infusion of recombinant brain-derived neurotrophic factor

Brain Res

(2000)

L. Belayev et al.

Middle cerebral artery occlusion in the rat by intraluminal sutureNeurological and pathological evaluation of an improved model

Stroke

(1996)

J.E. Black et al.

Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats

Proc Natl Acad Sci USA

(1990)

S.N. Blair et al.

Is physical activity or physical fitness more important in defining health benefits?

Med Sci Sports Exerc

(2001)

J.A. Boero et al.

Increased brain capillaries in chronic hypoxia

J Appl Physiol

(1999)

C.A. Campbell et al.

Preclinical models of stroke

Ding Y, Zhou Y, Li J, Lai Q, Diaz FG (2001) Long term neuroprotective effect of inhibiting poly (ADP-ribose) polymerase...

Y. Ding et al.

The distribution and morphology of LGN K pathway axons within the layers and CO blobs of owl monkey V1

Vis Neurosci

(1997)

Y. Ding et al.

Synaptic and neurochemical characterization of parallel pathways to the cytochrome oxidase blobs of primate visual cortex

J Comp Neurol

(1998)

Y. Ding et al.

Pre-reperfusion flushing of ischemic territory reduces inflammatory injury following transient middle cerebral artery occlusion in rats

Stroke

(2002)

Y. Ding et al.

Synaptic plasticity in thalamic nuclei enhanced by motor skill training in rat with transient middle cerebral artery occlusion

Neurol Res

(2003)

Ding Y, Li J, Luan X, Lai Q (2004) Motor balance and coordination training enhances functional outcome in rat with...

Y. Ding et al.

Pre-reperfusion flushing of ischemic territoryA therapeutic study in which histological and behavioral assessments were used to measure ischemia-reperfusion injury in rats with stroke

J Neurosurg

(2002)

R. Domenech et al.

Exercise induces early and late myocardial preconditioning in dogs

Cardiovasc Res

(2002)

R.J. Domenech et al.

Tachycardia preconditions infarct size in dogsRole of adenosine and protein kinase c

Circulation

(1998)

H. Ellekjaer et al.

Physical activity and stroke mortality in womenTen-year follow-up of the nord-trondelag health survey, 1984–1986

Stroke

(2000)

K.R. Evenson et al.

Physical activity and ischemic stroke riskThe atherosclerosis risk in communities study

Stroke

(1999)

M. Fisher et al.

Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats

J Cereb Blood Flow Metab

(1995)

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¹: Present address: University of Michigan Medical School.

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Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin

Abstract

Section snippets

Subjects

Neurological examination

Discussion

Acknowledgements

Neuroscience

Brain Res Mol Brain Res

Exp Neurol

Behav Brain Res

Exp Neurol

J Neurol Sci

Brain Res

Am J Cardiol

Brain Res

Arch Biochem Biophys

Arch Biochem Biophys

Eur J Pharmacol

Neuroscience

Behav Brain Res

Brain Res

Brain Res

Middle cerebral artery occlusion in the rat by intraluminal sutureNeurological and pathological evaluation of an improved model

Stroke

Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats

Proc Natl Acad Sci USA

Is physical activity or physical fitness more important in defining health benefits?

Med Sci Sports Exerc

Increased brain capillaries in chronic hypoxia

J Appl Physiol

Preclinical models of stroke

The distribution and morphology of LGN K pathway axons within the layers and CO blobs of owl monkey V1

Vis Neurosci

Synaptic and neurochemical characterization of parallel pathways to the cytochrome oxidase blobs of primate visual cortex

J Comp Neurol

Pre-reperfusion flushing of ischemic territory reduces inflammatory injury following transient middle cerebral artery occlusion in rats

Stroke

Synaptic plasticity in thalamic nuclei enhanced by motor skill training in rat with transient middle cerebral artery occlusion

Neurol Res

Pre-reperfusion flushing of ischemic territoryA therapeutic study in which histological and behavioral assessments were used to measure ischemia-reperfusion injury in rats with stroke

J Neurosurg

Exercise induces early and late myocardial preconditioning in dogs

Cardiovasc Res

Tachycardia preconditions infarct size in dogsRole of adenosine and protein kinase c

Circulation

Physical activity and stroke mortality in womenTen-year follow-up of the nord-trondelag health survey, 1984–1986

Stroke

Physical activity and ischemic stroke riskThe atherosclerosis risk in communities study

Stroke

Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats

J Cereb Blood Flow Metab