Abstract
Traumatic brain injury (TBI) survivors often suffer from long-lasting cognitive impairment that stems from hippocampal injury. Systemic administration of insulin-like growth factor-1 (IGF-1), a polypeptide growth factor known to play vital roles in neuronal survival, has been shown to attenuate posttraumatic cognitive and motor dysfunction. However, its neuroprotective effects in TBI have not been examined. To this end, moderate or severe contusion brain injury was induced in mice with conditional (postnatal) overexpression of IGF-1 using the controlled cortical impact (CCI) injury model. CCI brain injury produces robust reactive astrocytosis in regions of neuronal damage such as the hippocampus. We exploited this regional astrocytosis by linking expression of hIGF-1 to the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, effectively targeting IGF-1 delivery to vulnerable neurons. Following brain injury, IGF-1Tg mice exhibited a progressive increase in hippocampal IGF-1 levels which was coupled with enhanced hippocampal reactive astrocytosis and significantly greater GFAP levels relative to WT mice. IGF-1 overexpression stimulated Akt phosphorylation and reduced acute (1 and 3d) hippocampal neurodegeneration, culminating in greater neuron survival at 10d after CCI injury. Hippocampal neuroprotection achieved by IGF-1 overexpression was accompanied by improved motor and cognitive function in brain-injured mice. These data provide strong support for the therapeutic efficacy of increased brain levels of IGF-1 in the setting of TBI.
Highlights
Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide
Astrocyte-specific Overexpression of Insulin-like growth factor-1 (IGF-1) To verify astrocytic expression of IGF-1 we performed IGF-1 immunostaining in sham and brain-injured IGF-1 transgenic (IGF-1Tg) and WT mice, using an IGF-1 antibody that detects both mouse and human-IGF-1
After cortical impact (CCI) brain injury, IGF-1 immunostaining was markedly increased in IGF-1Tg mice throughout the hippocampus ipsilateral to the impact in cells with an astrocytic morphology
Summary
Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide. Controlled cortical impact (CCI) brain injury results in spatial memory impairment and neuronal damage in the cornu ammonis (CA-3), CA-1 and dentate gyrus subregions, the severity of which can be controlled by altering the depth of impact [9,10]. Owing to their pluripotent actions in the central nervous system (CNS), neurotrophic factors are considered potential therapeutic agents for TBI [11].
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