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Novel targets for valproic acid: up-regulation of
melatonin receptors and neurotrophic factors in C6 glioma cells
Rincon
Castro LM, Gallant
M, Niles
LP
Department of Psychiatry and Behavioural Neurosciences, McMaster University,
Hamilton, Ontario, Canada.
Valproic acid (VPA) is a potent anti-epileptic and effective mood
stabilizer.
It is known that VPA enhances central GABAergic activity and
activates the mitogen-activated protein kinase-extracellular
signal-regulated kinase (MAPK-ERK) pathway.
It can also inhibit various
isoforms of the enzyme, histone deacetylase (HDAC), which is associated with
modulation of gene transcription.
Recent in vivo studies indicate a
neuroprotective role for VPA, which has been found to up-regulate the
expression of brain-derived neurotrophic factor (BDNF) in the rat brain.
Given the interaction between the pineal hormone, melatonin, and GABAergic
systems in the central nervous system, the effects of VPA on the expression
of the mammalian melatonin receptor subtypes, MT(1) and MT(2), were examined
in rat C6 glioma cells.
The effects of VPA on the expression of glial cell
line-derived neurotrophic factor (GDNF) and BDNF were also examined.
RT-PCR
studies revealed a significant induction of melatonin MT(1) receptor mRNA in
C6 cells following treatment with 3 or 5 mm VPA for 24 h or 5 mm VPA for 48
h.
Western analysis and immunocytochemical detection confirmed that the
VPA-induced increase in MT(1) mRNA results in up-regulation of MT(1) protein
expression.
Blockade of the MAPK-ERK pathway by PD98059 enhanced the effect
of VPA on MT(1) expression, suggesting a negative role for this pathway in
MT(1) receptor regulation.
In addition, significant increases in BDNF, GDNF
and HDAC mRNA expression were observed after treatment with VPA for 24 or 48
h.
Taken together, the present findings suggest that the neuroprotective
properties of VPA involve modulation of neurotrophic factors and receptors
for melatonin, which is also thought to play a role in neuroprotection.
Moreover, the foregoing suggests that combinations of VPA and melatonin
could provide novel therapeutic strategies in neurological and psychiatric
disorders.
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