Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 73

auditory neurons [ 156 ] and were used in mice to infect damaged
spiral ganglion. Four weeks postinfection, stable production of
BDNF was observed and supported the survival of auditory neurons
by preventing their loss due to trophic factor deprivation-induced
apoptosis [ 157 ]. In a model of dissociated cultures of avian cochlear
neurons, the use of amplicons expressing BDNF promoted neuronal
survival similar to the maximal level seen by adding exogenous
BDNF [ 158 ].
The capability of BDNF and of glial cell line-derived neuro-
trophic factor (GDNF) to protect nigrostriatal neurons was com-
pared in a rat model of PD. According to this study, GDNF was
signifi cantly more effective than BDNF for both correcting behav-
ioral defi cits and protecting nigrostriatal dopaminergic neurons,
and the expression of both neurotrophic factors was no more effec-
tive than expressing only GDNF [ 44 ]. In a further study address-
ing the effect of this trophic factor, it was shown that intracerebral
administration of amplicons expressing GDNF, prior occlusion of
the middle cerebral artery, displayed neuroprotection of ischemic
injury. Treated animals showed reduced motor defi cits and, after 1
month, there was a reduction in tissue loss and in Glial Fibrillary
Acidic Protein (GFAP) and caspase-3 immune staining [ 159 ].
Amplicons expressing neurotrophin-3 (NT-3) were used in
murine cochlear explants models. After infection, the cochlear
explants were exposed to cisplatin to induce destruction of hair cells
and neurons in the auditory system. This toxicity, defi ned as ototox-
icity, is a major dose-limiting side effect of cisplatin chemotherapy
for cancer patients. Amplicon-mediated NT-3 transduction was
shown to attenuate the ototoxic action of cisplatin, demonstrating
the potency of NT-3 in protecting spiral ganglion neurons from
degeneration [ 160 ]. Moreover, amplicon-mediated NT-3 delivery
showed similar therapeutic properties in vivo in the peripheral audi-
tory system of the aged mouse [ 161 ]. Therefore, this approach
seems to be a promising treatment for prevention of chemical-
induced hearing disorders and potentially for hearing degeneration
due to normal aging. Also related to NT-3, amplicon vectors
expressing NR2D subunit of the NMDAR (HSVnr2d) were used
to demonstrate that the combined delivery of NT-3 and NR2D
strengthen monosynaptic connections in contused cords and
induced the appearance of weak but functional multisynaptic con-
nections in double hemisected cords, while treatment with either
NT3 or HSVnr2d alone failed to induce appearance of synaptic
responses through the hemisected region [ 162 ].
Apoptosis also plays a critical role in many neurological diseases,
including stroke, and many studies have shown that expression of
bcl-2 using amplicons can protect neurons in vivo from Adriamycin
treatment [ 163 ] or from different ischemic injuries [ 164 - 167 ].
Amplicon vectors expressing the inducible heat shock protein
HSP72 also can attenuate cerebral ischemic injury, even in