Background and Purpose
Gene therapy may be a promising approach for treatment of brain ischemia1, 2 although studies that revealed protective effects of gene therapy initiated after ischemia are limited. Our goal in this study was to examine the effect of gene transfer of interleukin-10 (IL-10), an anti-inflammatory cytokine, after induction of global brain ischemia.
Methods
Global brain ischemia was produced by bilateral carotid occlusion of aged spontaneously hypertensive rats (aged 15 to 22 months old, n=14) 3 . Cerebral blood flow (CBF) during ischemia was measured by laser Doppler flowmetry. Sixty minutes after ischemia, adenoviral vectors encoding human IL-10 (AdIL10, n=7) or vectors encoding β-galactosidase (Adβgal, n=7) were injected into the lateral ventricle. Five days after brain ischemia, cerebrospinal fluid (CSF) was withdrawn for measurement of interleukin-1β (IL-1β) and tissue necrosis factor-α (TNFα), and hippocampal neuronal damages were determined by hematoxyline-eosin staining and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) staining.
Results
Physiological parameters were not different between both treatment. CBF reduction during bilateral carotid occlusion (13.2±2.6%, mean±SEM, of the resting value for Adβgal and 12.5±1.8% for AdIL10) and the recovery after recirculation were not different between both groups. IL-10 gene transfer significantly (p<0.05) reduced the amount of IL-1β in CSF by 41% (Figure 1) and significantly (p<0.01) augmented that of TNFα by 49%. Furthermore, the IL-10 gene transfer after global ischemia significantly preserved hippocampal CA1 neurons (intact neurons: 95±18/mm for Adβgal, 174±20/mm for AdIL10, p<0.02) and significantly diminished TUNEL positive cells (128±27/mm for Adβgal, 61±12/mm for AdIL10, p<0.05).
Conclusions
Adenovirus-mediated gene transfer of IL-10 into the lateral ventricle initiated after global brain ischemia modulated production of cytokines and attenuated hippocampal neuronal damages. Therefore, gene transfer of IL-10 to the ischemic brain may be a promising approach for treatment of brain ischemia.