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Science Forum Index » Life Extension Forum » Involvement of PI3-K in neuroprotective effects of the...
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 Posted: Wed May 14, 2008 11:50 am |
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Pharmacol Rep. 2006 Nov-Dec;58(6):900-7. Links
Involvement of PI3-K in neuroprotective effects of the 1,25-
dihydroxyvitamin D3 analogue - PRI-2191.Regulska M, Le¶kiewicz M,
Budziszewska B, Kutner A, Basta-Kaim A, Kubera M, Jaworska-Feil L,
Lasoń W.
Department of Experimental Neuroendocrinology, Institute of
Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków,
Poland.
The active form of 1,25-dihydroxyvitamin D(3) prevents neuronal damage
in vitro and in vivo , however, it induces also hypercalcemia and
hyperphosphatemia. Side-chain-modified analogues of 1,25-
dihydroxyvitamin D(3), which show low calcemic activity, may be
potentially useful in the treatment of some neurodegenerative
diseases. Previously, we have found that PRI-2191 more potently than
1,25-dihydroxyvitamin D(3) protects human neuroblastoma (SH-SY5Y)
cells against hydrogen-peroxide-induced toxicity. In the present
study, we evaluated effects of two other 1,25-dihydroxyvitamin D(3)
analogues - PRI-1890 and PRI-1901 on the neuronal degeneration in the
same cell model. In line with the previous study, 24-h incubation with
hydrogen peroxide (0.5 mM) was toxic to cells, as evidenced by an
enhanced efflux of lactate dehydrogenase into the culture medium, and
these effects were prevented by PRI-1890 and PRI-1901 at concentration
of 5, 50 and 500 nM. Comparing the neuroprotective effects of
secosteroids, we found that all three analogues were efficient at
lower concentration than 1,25-dihydroxyvitamin D(3) and among them the
PRI-2191 showed the most evident concentration-dependent effect. In
the second part of this study, an involvement of mitogen-activated
protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K),
kinases which play a crucial role in neurodegenerative processes, in
neuroprotective action of 1,25 dihydroxyvitamin D(3) and its the most
potent analogue PRI-2191 has been investigated. The inhibitor of c-Jun
N-terminal kinase (JNK)-MAPK (SP600125, 1 microM), inhibitor of p38-
MAPK (SB-203580, 1 and 10 microM) and inhibitor of extracellular
signal-regulated kinase (ERK)-MAPK (PD-98059, 15 and 30 microM)
attenuated the hydrogen peroxide-induced toxicity. Moreover, PD-98059
(30 microM) enhanced neuroprotective effects of 1,25 dihydroxyvitamin
D(3) but not that of PRI-2191. In contrast, the inhibitor of PI3-K
(wortmannin, 10, 100 nM) did not affect hydrogen peroxide-induced cell
damage itself, however, it significantly antagonized the effect of
PRI-2191. On the other hand, wortmannin did not affect the
neuroprotective effects of 1,25 dihydroxyvitamin D(3) This suggests
that the activation of PI3-K/Akt signaling pathway plays an important
role in the mechanism of inhibitory action of PRI-2191 on hydrogen
peroxide-evoked toxicity in SH-SY5Y cells. Furthermore, these data
point to differential involvement of ERK-MAPK and PI3-K in
neuroprotective effects of 1,25 dihydroxyvitamin D(3) and its low-
calcemic analogue - PRI-2191.
PMID: 17220548 [PubMed - indexed for MEDLINE] |
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| Posted: Wed May 14, 2008 11:51 am |
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| Posted: Wed May 14, 2008 11:52 am |
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Pharmacol Rep. 2007 Jul-Aug;59(4):393-401. Links
Inhibitory effects of 1,25-dihydroxyvitamin D3 and its low-calcemic
analogues on staurosporine-induced apoptosis.Regulska M, Le¶kiewicz M,
Budziszewska B, Kutner A, Jantas D, Basta-Kaim A, Kubera M, Jaworska-
Feil L, Lasoń W.
Department of Experimental Neuroendocrinology, Institute of
Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków,
Poland.
The active form of vitamin D3 and some of its related compounds show
neuroprotective effects in various models of neuronal damage, however,
mechanism of their anti-apoptotic action has not been elucidated.
Therefore, the present study was designed to investigate the effects
of 1,25-dihydroxyvitamin D3 and its low-calcemic analogues, PRI-2191,
PRI-1890 and PRI-1901 on staurosporine-induced apoptosis in human
neuroblastoma SH-SY5Y cells. Twenty-four hour incubation with
staurosporine (1 microM) enhanced the caspase-3 activity, decreased
mitochondrial membrane potential and increased the number of apoptotic
cells as visualized by Hoechst staining. 1,25-Dihydroxyvitamin D3 and
PRI-2191 attenuated the staurosporine-induced caspase-3 activity at 5,
50 and 500 nM, whereas PRI-1890 and PRI-1901 were active only at
higher concentrations. Furthermore, 1,25-dihydroxyvitamin D3 (50 and
500 nM) and PRI-2191 (500 but not 50 nM) reversed the staurosporine-
evoked decrease in mitochondrial membrane potential. Hoechst and
calcein staining confirmed the neuroprotective effects of the
secosteroids under study. Further study revealed that a selective
inhibitor of phosphatidylinositol 3-kinase (PI3-K), wortmannin, at
concentration of 100 nM antagonized the effect of 1,25-
dihydroxyvitamin D3 and PRI-2191 on staurosporine-induced caspase-3
activation. These data indicate that 1,25-dihydroxyvitamin D3 and its
low-calcemic analogues at nanomolar concentrations inhibited
mitochondrial pathway of apoptosis in SH-SY5Y neuronal cells, though
with different potency. Moreover, the activation of PI3-K/Akt
signaling pathway appears to play a role in anti-apoptotic effects of
the secosteroids.
PMID: 17901567 [PubMed - indexed for MEDLINE] |
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