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Cerebellar stimulation reduces inducible nitric oxide synthase expression and protects brain from ischemia
E Galea1, E V Golanov, D L Feinstein
1Division of Neurobiology, Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021, USA. egalea@uic.educ
Abstract:
A focal infarction produced by occlusion of the middle cerebral artery (MCAO) in spontaneously hypertensive rats induced expression of inducible nitric oxide synthase (iNOS) mRNA, measured by competitive reverse transcription-polymerase chain reaction. The mRNA appeared simultaneously in the ischemic core and penumbra at 8 h, peaked between 14 and 24 h, and disappeared by 48 h. At 24 h, inducible nitric oxide synthase (iNOS)-like immunoreactivity was present in the endothelium of cerebral microvessels and in scattered cells, probably representing leukocytes or activated microglia. Electrical stimulation of the cerebellar fastigial nucleus (FN) for 1 h, 48 h before MCAO, reduced infarct volumes by 45% by decreasing cellular death in the ischemic penumbra. It also reduced by >90% the expression of iNOS mRNA and protein in the penumbra, but not core, and decreased by 44% the iNOS enzyme activity. We conclude that excitation of neuronal networks represented in the cerebellum elicits a conditioned central neurogenic neuroprotection associated with the downregulation of iNOS mRNA and protein. This neuroimmune interaction may, by blocking the expression of iNOS, contribute to neuroprotection.
Insights
Electrical stimulation of the brain
Area of Science:
- Neuroscience
- Immunology
- Cardiovascular Science
Background:
- Middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats induces inducible nitric oxide synthase (iNOS) expression.
- iNOS mRNA appears in the ischemic core and penumbra within 8 hours, peaking at 14-24 hours.
- iNOS immunoreactivity is found in cerebral microvessels and immune cells (leukocytes, microglia) 24 hours post-MCAO.
Purpose of the Study:
- To investigate the neuroprotective effects of cerebellar fastigial nucleus (FN) stimulation prior to MCAO.
- To determine the impact of FN stimulation on iNOS expression and activity in ischemic stroke models.
- To elucidate the role of neuroimmune interactions in conditioned central neuroprotection.
Main Methods:
- Induction of focal cerebral infarction via MCAO in spontaneously hypertensive rats.
- Measurement of iNOS mRNA expression using competitive reverse transcription-polymerase chain reaction.
- Assessment of iNOS-like immunoreactivity and enzyme activity.
- Electrical stimulation of the cerebellar fastigial nucleus (FN) 48 hours before MCAO.
Main Results:
- FN stimulation reduced infarct volume by 45% through decreased cellular death in the ischemic penumbra.
- FN stimulation significantly downregulated iNOS mRNA and protein expression (>90%) in the penumbra, but not the core.
- iNOS enzyme activity was reduced by 44% following FN stimulation.
Conclusions:
- Cerebellar FN stimulation elicits conditioned central neurogenic neuroprotection.
- This neuroprotection is associated with the downregulation of iNOS mRNA and protein in the ischemic penumbra.
- The neuroprotective mechanism involves a neuroimmune interaction that may block iNOS expression, contributing to reduced stroke damage.