Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Drug
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Target Concepts:
Gene/Protein
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Query: UMLS:C0917798 (
cerebral ischemia
)
17,036
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Domperidone
(
DOM
), a peripheral dopamine D2 receptor antagonist, is a substrate of P-glycoprotein (P-gp). Therefore, the transport of
DOM
into the brain may be restricted by P-gp function at the blood-brain barrier, and when the function of P-gp is impaired by ATP depletion under conditions of brain ischaemia (e.g. cerebral thrombosis), side-effects may be induced as a result of increased distribution of
DOM
into the brain. In this study, we investigated the effects of brain ischaemia and verapamil, a P-gp inhibitor, on the permeability coefficient-surface area product (PS values) of
DOM
across the blood-brain barrier by using an in-situ rat brain perfusion technique. The PS values of
DOM
were increased 3.4- and 3.6-fold after brain ischaemia for 10 and 20 min, respectively. Furthermore, co-administration of verapamil significantly increased the PS values of
DOM
by 42.6- and 43.3-fold in the normal and ischaemia groups, respectively. Brain vascular volume was not affected by ischaemia or verapamil. These results show that the transport of
DOM
into the brain is restricted by P-gp and that the brain distribution of
DOM
can be increased by
cerebral ischaemia
or co-administration of a P-gp inhibitor.
...
PMID:Distribution of domperidone into the rat brain is increased by brain ischaemia or treatment with the P-glycoprotein inhibitor verapamil. 1200 68
Duloxetine
(DXT), a serotonin/norepinephrine reuptake inhibitor, is widely used for the treatment of major depressive disorders. In the present study, we investigated the neuroprotective effect of pre-treated DXT in the hippocampal CA1 region following transient global
cerebral ischemia
. Pre-treatment with 40mg/kg DXT protected pyramidal neurons in the CA1 region from ischemia-reperfusion injury. In addition, pre-treatment with DXT reduced ischemia-induced activations of microglia and astrocytes in the ischemic CA1 region. On the other hand, we found that pre-treatment with DXT did not increase 4-hydroxy-2-noneal (a marker for lipid peroxidation) and significantly increased the expression of Cu, Zn-superoxide dismutase, an antioxidant, in the CA1 pyramidal neurons compared with non-treated those after ischemia-reperfusion. These results indicate that pre-treated DXT has neuroprotective effect against transient global
cerebral ischemia
and suggest that the neuroprotective effect of DXT may be due to the attenuation of ischemia-induced glial activation as well as the decrease of oxidative stress.
...
PMID:Pretreated duloxetine protects hippocampal CA1 pyramidal neurons from ischemia-reperfusion injury through decreases of glial activation and oxidative stress. 2777 65
Activation of transient receptor potential melastatin 2 (TRPM2), an oxidative stress-sensitive Ca
2+
-permeable channel, contributes to the aggravation of
cerebral ischemia
-reperfusion (CIR) injury. Recent studies indicated that treatment with the antidepressant duloxetine for 24 hours (long term) attenuates TRPM2 activation in response to oxidative stress in neuronal cells. To examine the direct effects of antidepressants on TRPM2 activation, we examined their short-term (0-30 minutes) treatment effects on H
2
O
2
-induced TRPM2 activation in TRPM2-expressing human embryonic kidney 293 cells using the Ca
2+
indicator fura-2.
Duloxetine
exerted the strongest inhibitory effects on TRPM2 activation among the seven antidepressants tested. These inhibitory effects appeared to be due to the inhibition of H
2
O
2
-induced TRPM2 activation via an open-channel blocking-like mechanism, because duloxetine reduced the sustained phase but not the initial phase of increases in intracellular Ca
2+
concentrations. In a whole-cell patch-clamp study, duloxetine reduced the TRPM2-mediated inward current during the channel opening state. We also examined the effects of duloxetine in a mouse model of CIR injury. The administration of duloxetine to wild-type mice attenuated CIR injury, similar to that in
Trpm2
knockout (KO) mice. The administration of duloxetine did not reduce CIR injury further in
Trpm2
KO mice, suggesting that it exerts neuroprotective effects against CIR injury by inhibiting TRPM2 activation. Regarding drug repositioning, duloxetine may be a useful drug in reperfusion therapy for ischemic stroke because it has already been used clinically in therapeutics for several disorders, including depression.
...
PMID:Protective Effects of Duloxetine against Cerebral Ischemia-Reperfusion Injury via Transient Receptor Potential Melastatin 2 Inhibition. 3052 61
