Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 74

postischemia situations, when introduced in rat striatum [ 168 ].
Moreover, amplicons expressing HSP72 also protected neurons in
CA1 hippocampal region from ischemia; this protection would be
mediated, at least in part, by increased expression of bcl-2 [ 169 ].
Another study used amplicons to overexpress HSP70 in order to
protect cultured hippocampal neurons from HIV gp120 induced
neurotoxicity [ 170 ].
Amplicons expressing the rat brain glucose transporter were
used to demonstrate that (1) they can enhance glucose uptake in
adult rat hippocampus and in hippocampal cultures [ 171 ], (2) such
vectors can maintain neuronal metabolism and reduce the extent of
neuron loss in cultures after a period of hypoglycemia [ 172 ], and
(3) these vectors protected cultured hippocampal, spinal cord, and
septal neurons against various necrotic insults, including hypogly-
cemia, glutamate, and 3-nitropropionic acid [ 173 ].
Increases in cytoplasmic Ca 2+ concentration can lead to neuro-
toxicity and neuronal death. The increase of Ca 2+ can be induced
by neurological trauma associated with aging and some neurologi-
cal diseases. It was shown, both in vitro and in vivo, that amplicons
expressing the calcium-binding protein calbindin D28K decreased
the neurotoxic impact of Ca 2+ [ 174 , 175 ].
Lastly, generation of ROS and oxidative damage plays an
important role in neuron death, and vectors expressing different
antioxidant enzymes were used to counteract oxidative damages.
Amplicons expressing catalase or glutathione peroxidase, two
enzymes involved in degradation of hydrogen peroxide, were
shown to decrease neurotoxicity induced by different agents in
primary cultures of hippocampus or cerebral cortex cells [ 176 ].
A further study using amplicons to express the antioxidant enzyme,
Cu-Zn-SOD, showed that these vectors were able to protect hip-
pocampal neurons through the induction of glutathione peroxi-
dase, though only in the case of neurons treated with sodium
cyanide. The authors pointed out that when neurons were treated
with kainic acid, another classical ROS inducer, the effect of the
amplicon actually worsen the toxic effects, raising a cautionary
note concerning gene therapy against oxidative damages [ 177 ].
Amplicons expressing glutamic acid decarboxylase (GAD67) were
able to protect nondifferentiated cortical neurons from glutamate
toxicity mediated by oxidative stress [ 178 ].

14.4 Brain Tumors

Amplicons have been widely used to study or to treat experimental
cancers, both in brain and in other tissues, using several anticancer
strategies. Since these vectors can effi ciently deliver genes to cancer
cells but are diluted during successive cell divisions, most studies
have used acute approaches, like direct cell killing using prodrugs
or toxic proteins or induction of apoptosis. In rodent and human
glioma cell lines, the fusion protein 4B1:EGFP was expressed from
amplicons, in an attempt to combine advantages of expression of