Defective Herpes Simplex Virus Vectors Expressing the Rat Brain Stress‐Inducible Heat Shock Protein 72 Protect Cultured Neurons from Severe Heat Shock

Abstract

Recently, preinduction of the heat shock re-The preferential induction ofhsps during stress amid sponse has been shown to protect CNS neurons under-an overall decrease in protein synthesis suggests a progoing various stressful insults, e.g., heat, ischemia, or tective role for them. As more correlative support for exposure to excitotoxins. However, it is not known which protection, some neurons that mount a strong hsp reof the proteins induced by the heat shock response medi-sponse preferentially survive stressors (Vass et al.

The HSV-2 protein ICP10PK prevents neuronal apoptosis and loss of function in an in vivo model of neurodegeneration associated with glutamate excitotoxicity

“…Strategies to attenuate the neurological symptoms of acute injury are of great clinical importance and their development is the subject of major research interest (Harvey et al, 2003). Intrastriatal delivery of Bcl-2, GDNF or Hsp72 with HSV-1 based vectors was previously shown to protect a small percentage of neurons from ischemic death (Linnik et al, 1995;Lawrence et al, 1996;Fink et al, 1997;Wang et al, 1997;Yenari et al, 1998;Antonawich et al, 1999;Harvey et al, 2003), but at least one such vector, caused inflammation and neurotoxicity (Monville et al, 2004). Genome-free HSV-based vectors were constructed (amplicons), and their safety improved by the development of a helper-free delivery system that supports the replication and packaging of co-transfected amplicon DNA (Olschowka et al, 2003).…”

“…Most importantly, for therapy to be effective, the surviving neurons must retain normal function (Dumas et al, 2001). In most of the aforementioned studies, neuronal function was not examined (Linnik et al, 1995;Lawrence et al, 1996;Fink et al, 1997;Wang et al, 1997;Yenari et al, 1998;Antonawich et al, 1999), and when examined, neurons were found to be dysfunctional (Harvey et al, 2003).…”

“…Indeed, HSV can cross synapses infecting each neuron in a pathway (Geller et al, 1991;Glorioso et al, 1994). Recent attempts to minimize ischemic damage have used HSV-1 based vectors to deliver genes encoding a variety of anti-apoptotic proteins such as Bcl-2, glial-derived neurotrophic factor (GDNF) or heat shock protein 72 (Hsp72) (Linnik et al, 1995;Lawrence et al, 1996;Fink et al, 1997;Wang et al, 1997;Yenari et al, 1998;Antonawich et al, 1999;Harvey et al, 2003). However, safety concerns linger because HSV-1 has pro-apoptotic activity in the CNS and can cause encephalitis in immunocompetent human adults (Perkins, 2002;.…”

HSV-mediated delivery of virally derived anti-apoptotic genes protects the rat hippocampus from damage following excitotoxicity, but not metabolic disruption

“…20 For the purpose of this investigation, the activity of ␤-galactosidase was used as a marker to confirm stable transduction of cells and subsequent expression of amplicon plasmids. The coincidence of expression of genes driven from the ␣4 and ␣22 promoters has been quantified previously to be >98%, 21 and thus ␤-galactosidase staining was utilized as a marker for infection. The monocistronic control vector used in these studies expresses the ␤-galactosidase reporter gene under the control of the ␣4 promoter (Figure 1b).…”

Brain distribution of carboxy terminus of Hsc70-interacting protein (CHIP) and its nuclear translocation in cultured cortical neurons following heat stress or oxygen–glucose deprivation

“…Induction of HSP70 was seen in models of ischemic tolerance (Chen and Simon 1997;Kirino 2002;Yenari et al 1999a), and inhibition of HSP70 led to partial inhibition of tolerance (Kirino 2002). Virally mediated HSP70 overexpression in cultured neurons protected these cells from heat stress (Fink et al 1997). Viral delivery of HSP70 pre-ischemia was neuroprotective in rat models of stroke (Kelly et al 2002;Yenari et al 1998).…”