Astrocyte targeted overexpression of Hsp72 or SOD2 reduces neuronal vulnerability to forebrain ischemia

Abstract

Brief forebrain ischemia is a model of the delayed hippocampal neuronal loss seen in patients following cardiac arrest and resuscitation. Previous studies demonstrated that selective dysfunction of hippocampal CA1 subregion astrocytes occurs hours to days before delayed neuronal death. In this study we tested the strategy of directing protection to astrocytes to protect neighboring neurons from forebrain ischemia. Two well-studied protective proteins, heat shock protein 72 (Hsp72) or superoxide dismutase 2 (SOD2), were genetically targeted for expression in astrocytes using the astrocyte-specific human glial fibrillary acidic protein (GFAP) promoter. The expression constructs were injected stereotacticly immediately above the hippocampal CA1 region on one side of the rat brain two days prior to forebrain ischemia. Cell type specific expression was confirmed by double label immunohistochemistry. When the expression constructs were injected two days before transient forebrain ischemia, the loss of CA1 hippocampal neurons observed seven days later was significantly reduced on the injected side compared with controls. This neuroprotection was associated with significantly better preservation of astrocyte glutamate transporter-1 immunoreactivity at 5-h reperfusion and reduced oxidative stress. Improving the resistance of astrocytes to ischemic stress by targeting either the cytosolic or mitochondrial compartment was thus associated with preservation of CA1 neurons following forebrain ischemia. Targeting astrocytes is a promising strategy for neuronal preservation following cardiac arrest and resuscitation.

Inner ear supporting cells protect hair cells by secreting HSP70

“…In addition, olfactory sensory neurons are protected by HSP induction (40). Targeted overexpression of HSP70 in astrocytes protects CA1 hippocampal neurons from death caused by transient forebrain ischemia (41). Consistent with our finding that stress-induced HSP70 induction is specific to supporting cells, a recent report showed that noise trauma resulted in increased HSP70 immunoreactivity in Deiters' cells (42).…”

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…Hsp70 overexpression significantly potentiated the activities of glutathione peroxidase and glutathione reductase, leading to a higher GSH/GSSG ratio, attenuated ROS production, and improved cell survival under conditions of MECHANISMS AND THERAPIES IN DIABETIC PERIPHERAL NEUROPATHY hypoxia and glucose deprivation (Guo et al, 2007). Likewise, overexpression of Hsp70 in astrocytes increased mitochondrial function and decreased neuronal injury after basal forebrain ischemia (Xu et al, 2010). Consistent with this result, KU-32 increased the translation of Hsp70, as well as other chaperones and MnSOD in hyperglycemically stressed sensory neurons.…”

Glial Cells, Inflammation and Heat Shock Proteins in Cerebral Ischemia

“…Astrocytes in the CA1 region of the brain, which is particularly sensitive to forebrain ischemia, lose glutamate transporter expression and activity prior to the death of CA1 neurons Ouyang et al, 2007;Yeh et al, 2005). We have shown that astrocyte-targeted overexpression of Hsp72 not only protects CA1 neurons from transient forebrain ischemia, but also preserves GLT-1 immunoreactivity in the region (Xu et al, 2010) suggesting a possible mechanism for the observed protection.…”