Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy

Abstract

Brain areas damaged by stroke and seizures express high levels of the 72-kd heat shock protein (HSP72). Whether HSP72 represents merely a marker of stress or plays a role in improving neuron survival in these cases has been debated. Some induced tolerance experiments have provided correlative evidence for a neuroprotective effect, and others have documented neuroprotection in the absence of HSP72 synthesis. We report that gene transfer therapy with defective herpes simplex virus vectors overexpressing hsp72 improves neuron survival against focal cerebral ischemia and systemic kainic acid administration. HSP72 overexpression improved striatal neuron survival from 62.3 to 95.4% in rats subjected to 1 hour of middle cerebral artery occlusion, and improved survival of hippocampal dentate gyrus neurons after systemic kainic acid administration, from 21.9 to 64.4%. We conclude that HSP72 may participate in processes that enhance neuron survival during transient focal cerebral ischemia and excitotoxin-induced seizures.

Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat

“…Infarct volumes obtained with our procedure are very similar to those found with longer periods of ischemia [13,51,76]. Several studies have also found large infarct areas using only 1 h of transient focal ischemia and have used this model to investigate the effects of different compounds in experimental ischemic stroke in the rat [58,67,74,80]. Since nimesulide's neuroprotection could easily result from drug-induced hypothermia rather than a specific pharmacological effect, we strictly monitored rectal temperature and found that nimesulide did not modify this physiological variable (data not shown).…”

“…Other therapeutic strategies for stroke include hypothermia [20,65,81], antioxidants [7,13,14,64], blockade of excessive synaptic Zn 2+ release [75], antiapoptotic strategies [26,53], administration of growth factors [1,40], erythropoietin [67], recombinant human interleukin-1 receptor antagonist [47], statins [73], gene therapy [80,81] and approaches involving transfer of new cells, such as stem cells, and neuronal precursors cells [1,46,63].…”

Gene therapy in the CNS

“…199 Expression of 72-kDa heat shock protein via HSV vector also improved neuron survival against transient focal ischemia. 200 Ad vectors have also been shown effectively to transfer genes to cerebral blood vessels and overlying meninges, 201 and transfer of genes for enzymes with vasodilator function may also attenuate ischemic damage. Ex vivo therapy for ischemia includes transplantation of fibroblasts genetically modified to secrete NGF into the hippocampus, which protected neurons within CA1 and CA2 regions from damage.…”

“…Exploratory modalities have included: delivery of heat shock protein (HSP72) via an HSV amplicon vector which protect hippocampal neurons from kainic acid toxicity; 200 Ad-mediated delivery of glutamic acid decarboxylase to increase synthesis of the inhibitory neurotransmitter GABA; 240 and lipofectin-mediated delivery of cholecystokinin, an anticonvulsant and anti-opioid neuropeptide, to the ventricles to alleviate (temporarily) audiogenic seizures. 241 Endocrine functions Viral vectors have also been used as tools for examining the role of hormonal replacement therapy in distinct neuroendocrine and/or sensory pathways.…”

Novel targets for CNS gene therapy

“…Although as yet undeveloped as a gene therapy target it would be wise to concurrently design and evaluate vectors capable of transduction of the desired substrate. [5][6][7] Arteriovenous malformations (AVMs) represent another potentially novel target for CNS gene therapy. These lesions, reflecting dysgenesis of the vasculature, have the proclivity to bleed and produce morbidity (including seizures) and death.…”