Astrocyte-specific insulin-like growth factor-1 gene transfer in aging female rats improves stroke outcomes.
Middle aged female rats sustain larger stroke infarction and disability than younger female rats. This older group also shows age-related reduction of insulin like growth factor (IGF)-1 in serum and in astrocytes, a cell type necessary for poststroke recovery. To determine the impact of astrocytic IGF-1 for ischemic stroke, these studies tested the hypothesis that gene transfer of IGF-1 to astrocytes will improve stroke outcomes in middle aged female rats. Middle aged (10-12 month old), acyclic female rats were injected with recombinant adeno-associated virus serotype 5 (AAV5) packaged with the coding sequence of the human (h)IGF-1 gene downstream of an astrocyte-specific promoter glial fibrillary acidic protein (GFAP) (AAV5-GFP-hIGF-1) into the striatum and cortex. The AAV5-control consisted of an identical shuttle vector construct without the hIGF-1 gene (AAV5-GFAP-control). Six to eight weeks later, animals underwent transient (90 min) middle cerebral artery occlusion via intraluminal suture. While infarct volume was not altered, AAV5-GFAP-hIGF-1 treatment significantly improved blood pressure and neurological score in the early acute phase of stroke (2 days) and sensory-motor performance at both the early and late (5 days) acute phase of stroke. AAV5-GFAP-hIGF-1 treatment also reduced circulating serum levels of GFAP, a biomarker for blood brain barrier permeability. Flow cytometry analysis of immune cells in the brain at 24 hr poststroke showed that AAV5-GFAP-hIGF-1 altered the type of immune cells trafficked to the ischemic hemisphere, promoting an anti-inflammatory profile. Collectively, these studies show that targeted enhancement of IGF-1 in astrocytes of middle-aged females improves stroke-induced behavioral impairment and neuroinflammation.
Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, Texas, 77807.
Andre K
AK
Okoreeh
Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, Texas, 77807.
Shameena
S
Bake
Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, Texas, 77807.
Farida
0000-0002-6960-3411
F
Sohrabji
D000375:Aging; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001253:Astrocytes / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D020520:Brain Infarction / Q000209:etiology / Q000628:therapy; D004195:Disease Models, Animal; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005260:Female; D020233:Gait Disorders, Neurologic / Q000209:etiology / Q000628:therapy; D018737:Hand Strength / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000628:therapy*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D009068:Movement / Q000502:physiology; D009460:Neurologic Examination; D051381:Rats; D017207:Rats, Sprague-Dawley; D057897:Reflex, Righting / Q000502:physiology; D014161:Transduction, Genetic / Q000379:methods*
D015703:Antigens, CD; D027341:Excitatory Amino Acid Transporter 1; C583557:IGF1 protein, human; C493392:Slc1a3 protein, rat; D007334:Insulin-Like Growth Factor I
M1/M2 activation; blood brain barrier; middle cerebral artery occlusion; sensory motor tasks