Mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathway, also known as MEK pathway, is reported to be associated with the cell proliferation, differentiation, migration, senescence and apoptosis[3]. SL327 inhibits MEK1 and MEK2, with IC50 values of 0.18 μM and 0.22 μM, respectively[4]. In vivo, the study showed that the combination of SL327 with sunitinib malate induced significant additive suppression of doxorubicin-resistant anaplastic thyroid carcinoma (ATC) tumor growth[4]. SL327 attenuates phosphorylated MAPK levels in a dose-dependent manner in mice. Administration of 10, 30, or 50 mg/kg SL327 significantly attenuates p42 phospho-MAPK levels (F=20.90, P<0.0001; 10 mg/kg SL327 vs. vehicle, P<0.05, and 30 and 50 mg/kg SL327 vs. vehicle, P<0.001). Injection with 30 or 50 mg/kg SL327 also significantly reduces p44 phospho-MAPK levels (F=5.627, P<0.005; 30 mg/kg vs. vehicle, P<0.05, and 50 mg/kg SL327 vs. vehicle, P<0.01)[5].
SL327 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Mixed neuron–glia cortical cell cultures
30 µM
30 minutes
SL327 significantly reduced heme oxygenase (HO) activity in cultures
Neuropharmacology. 2009 Apr;56(5):922-8.
MGE cells
10 µM
7 days
To assess the effect of MEK inhibitor SL327 on LHX6 expression, found that SL327 restored LHX6 expression in Nf1 cKO CINs
Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):6189-6195.
Recombinant HO-1 and HO-2
30 µM
SL327 had no significant effect on the activity of recombinant HO-1 or HO-2
Neuropharmacology. 2009 Apr;56(5):922-8.
SL327 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Ethanol withdrawal anxiety model
Intracerebroventricular injection
1 µg/5 µl
Administered 30 min prior to each of two stress sessions
Blocked stress facilitation of ethanol withdrawal anxiety
Inhibition of ERK1/2 signaling, downregulation of GSK-3β (Ser9) phosphorylation
Mar Drugs. 2019 Mar 15;17(3):168
Rats
Morphine dependence model
Intraperitoneal injection
100 mg/kg
Once, 1 hour before naloxone injection
To evaluate the effect of SL327 (a selective MEK inhibitor) on TH phosphorylation at Ser31 during morphine withdrawal. Results showed that SL327 significantly reduced the phosphorylation levels of TH at Ser31.
Br J Pharmacol. 2008 Sep;155(1):73-83
Rats
Morphine dependence model
Intraperitoneal injection
100 mg/kg
1 hour before administration
SL327 (a selective inhibitor of MEK) at doses that reduced the augmented pERK levels in the PVN, did not attenuate the rise in pCREB immunoreactivity or plasma corticosterone secretion.
Br J Pharmacol. 2011 Jun;163(4):857-75
Sprague-Dawley rats
Morphine dependence model
Intraperitoneal injection
100 mg/kg
Single dose, 1 hour before morphine withdrawal
SL327 significantly inhibited the increase in phosphorylation of ERK1/2 and c-Fos expression in cardiac tissues induced by morphine withdrawal.
Br J Pharmacol. 2007 Jul;151(6):787-97
Mice
Neonatal mouse hypoxic-ischemic brain injury model
Intraperitoneal injection
133 μg/g
Single injection, administered 20 min before or 1 h after HI insult
SL327 significantly reduced cell death and microglial activation, showing neuroprotective effects in both pre- and post-treatment
J Physiol. 2018 Dec;596(23):6043-6062
Nude mice
Subcutaneous tumor model
Intraperitoneal injection
3 mg/kg/day
Once daily, continuous treatment
Inhibited tumorigenicity of melanoma cells
Front Cell Dev Biol. 2020 Dec 17;8:607757
Mice
Conditioned place preference (CPP) model
Intraperitoneal injection
30 mg/kg
Single administration, 1 hour before cocaine reexposure
Blockade of the ERK pathway during drug reexposure erases previously acquired cocaine-induced CPP and associated protein phosphorylation responses
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2932-7
Mice
Myshkin mouse model
Intraperitoneal injection
30 mg/kg
Acute administration
SL327 reduced the total distance traveled in the open field, duration on the open arms, and exploratory head dips in the EPM in Myk/+ mice.
Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18144-9
Klotho mutant mice
Klotho mutant mouse model
Intraperitoneal injection
5 or 10 mg/kg
Injected 30 min before the memory trial
SL327 significantly counteracted melatonin-mediated increases in ERK phosphorylation, Nrf2 nuclear translocation and DNA-binding activity, and GCL mRNA expression, and reversed melatonin-mediated up-regulation of the GSH/GSSG ratio and memory enhancement.
Int J Neuropsychopharmacol. 2014 Dec 30;18(6):pyu105
Mice
Wild-type mice
Intraperitoneal injection
50 and 100 mg/kg
Single administration
SL327 inhibits morphine-induced locomotor activity in a dose-dependent manner
Neuropsychopharmacology. 2011 Feb;36(3):551-8
Mice
TgNTRK3 mouse model
Intraperitoneal injection
50 mg/kg
Single dose
SL327 inhibited ERK phosphorylation, blocking NT3-induced rescue of fear extinction memory
Neuropsychopharmacology. 2017 Jan;42(2):462-472
CD-1 mice
Conditioned place preference (CPP) and locomotor activity measurements
Intraperitoneal injection
50 mg/kg
Administered 1 hour before
SL327 completely abolished the MDMA-induced conditioned place preference and hyperlocomotor activity, indicating a critical role of the ERK pathway in these behavioral responses.
Br J Pharmacol. 2003 Nov;140(5):831-8
Rats
Formalin-induced acute inflammation model
Intraperitoneal injection
50 mg/kg
Single dose, 30 minutes before formalin injection
Inhibition of ERK activity reduced formalin-induced p-ERK, p-MSK1, and p-H3S10, demonstrating that spinal p-MSK1 and p-H3S10 were at least partly downstream of ERK signalling.
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