Everything about Mibolerone(Cheque drops)
| 2.Biochem/physiol Actions–CAS:1101854-58-3
| 3.JZL-184 Dosage Base on Weight
| 4.JZL-184 Effects on Neuroprotective
| 5. JZL-184 Improves Behavior and Neural Properties
| 6.Buy JZL-184 from Reliable JZL-184 Suppliers online
JZL 184 video
I.JZL 184 basic Characters:
|Color:||Pale yellow solid|
JZL-184(1101854-58-3) is a potent and selective inhibitor of MAGL with IC50 of 8 nM and 4 μM for inhibition of MAGL and FAAH in mouse brain membranes respectively. IC50 value: 8 nM Target: MAGL inhibitor in vitro: JZL-184 prolongs DSE in Purkinje neurons in cerebellar slices and DSI in CA1 pyramidal neurons in hippocampal slices. JZL-184 is more potent in inhibiting mouse MAGL than rat MAGL. in vivo: When administered to mice at 16 mg/kg, intraperitoneally, JZL-184 reduces MAGL activity by 85%, elevates brain 2-AG levels by 8-fold, and elicits analgesic activity in a variety of pain assays that qualitatively mimics direct central cannabinoid (CB1) agonists. Acute administration of JZL-184 to FAAH(-/-) mice enhanced the magnitude of a subset of cannabimimetic responses, repeated JZL-184 treatment led to tolerance to its antinociceptive effects, cross-tolerance to the pharmacological effects of Δ-tetrahydrocannabinol, decreases in CB1 receptor agonist-stimulated guanosine 5′-O-(3-[(35)S]thio)triphosphate binding, and dependence as indicated by rimonabant-precipitated withdrawal behaviors, regardless of genotype.
Endocannabinoids such as 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (AEA) are biologically active lipids that are involved in a number of synaptic processes including activation of cannabinoid receptors. Monoacylglycerol lipase (MAGL) is a serine hydrolase responsible for the hydrolysis of 2-AG to arachidonic acid and glycerol, thus terminating its biological function. JZL-184 is a potent and selective inhibitor of monoacylglycerol lipase (MAGL) that displays IC50 values of 8 nM and 4 µM for inhibition of MAGL and fatty acid amide hydrolase in mouse brain membranes, respectively.1 When administered to mice at 16 mg/kg, intraperitoneally, JZL-184 reduces MAGL activity by 85%, elevates brain 2-AG levels by 8-fold, and elicits analgesic activity in a variety of pain assays that qualitatively mimics direct central cannabinoid (CB1) agonists.
JZL -184 Basic Characters
|Appearance||Pale yellow solid|
|Solubility||Soluble in DMSO (10mg/ml)|
JZL-184 selectively inhibits MAGL, the enzyme predominantly responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Anandamide and 2-AG are the two endogenous endocannabinoids that activate the cannabinoid receptors CB1 and CB2. Anandamide is predominantly metabolized by fatty acid amide hydrolase (FAAH), whereas monoacylglycerol lipase (MAGL) is thought to be the enzyme primarily responsible for the degradation of 2-AG. It is difficult to separate the activities of the two because most currently available inhibitors of MAGL are not selective, and also inhibit FAAH or other enzymes. JZL-184 is the first selective inhibitor of MAGL with nanomolar portency and over 200-fold selectivity for MAGL vs FAAH. When administered to mice, JZL-184 increased levels of 2-arachidonoylglycerol in the brain by about 8-fold, with no effect on levels of anandamide.
To compare the effects of repeated administration of low versus high doses of JZL-184 on CB1 receptor activity in the brain, mice were injected with varying doses over a 25-fold range or vehicle for 5 consecutive days. CB1 receptor–mediated G-protein activation was examined using concentration-effect curves of CP55,940–stimulated GTPγS binding in membranes prepared from mouse brain homogenates. As shown in Fig. 1A, repeated dosing with 16 and 40 mg/kg JZL184 produced, respectively, 46 and 56% reductions in maximal CP55,940-stimulated G-protein activity (Emax), with no effect of either JZL-184 dose on CP55,940 EC50 values. In contrast, low JZL184 doses (1.6, 4, or 8 mg/kg) did not significantly affect CP55,940 Emax or EC50 values. To determine whether effects of JZL-184 on CB1 receptor–mediated G-protein activation were associated with decreased CB1 receptor levels, saturation binding analysis with the CB1-selective antagonist SR141716A was conducted in mice repeatedly administered JZL-184 (1.6, 4, 16, or 40 mg/kg) or vehicle, as described earlier. Repeated dosing with 16 and 40 mg/kg JZL184 reduced R141716A Bmax values by 30 and 35%, respectively. However, repeated administration of low doses of JZL-184 did not significantly alter SR141716A Bmax values. BasalGTPγS binding was not affected by repeated treatment with any dose of JZL-184. Moreover,SR141716A KD values were unaffected by repeated treatment with any of the JZL-184 doses tested.
Growing evidence suggests that the endocannabinoid system plays a role in neuroprotection in Parkinson’s disease. Recently, we have shown the neuroprotective effect of monoacylglycerol lipase (MAGL) inhibition with JZL-184 in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. However, further investigation is needed to determine the neuroprotective mechanisms of the endocannabinoid system on the nigrostriatal pathway. The aim of this work was to investigate whether the neuroprotective effect of JZL-184 in mice could be extended to an in vitro cellular model to further understand the mechanism of action of the drug. The SH-SY5Y cell line was selected based on its dopaminergic-like phenotype and its susceptibility to 1-methyl-4-phenylpyridinium iodide (MPP+) toxicity. Furthermore, SH-SY5Y cells express both cannabinoid receptors, CB1 and CB2. The present study describes the neuroprotective effect of MAGL inhibition with JZL-184 in SH-SY5Y cells treated with MPP+. The JZL-184 effects in cell survival was blocked by AM630, a CB2 receptor antagonist, and it was mimicked with JWH133, a CB2 receptor agonist. Rimonabant, a CB1 receptor antagonist, did not affect JZL-184-induced cell survival. These results demonstrate that the neuroprotective effect of MAGL inhibition with JZL-184 described in animal models of Parkinson’s disease could be extended to in vitro models such as SH-SY5Y cells treated with MPP+. This represents a useful tool to study mechanisms of neuroprotection mediated by MAGL inhibition, and we provide evidence for the possible involvement of CB2 receptors in the improvement of cell survival.
(1) Abstract on Inhibitor JZL-184(1101854-58-3)
Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL-184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL-184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL-184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL-184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL-184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL-184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS.
(2) Discussion on JZL-184 Effects
Genetic alterations or pharmacological treatments affecting brain levels of endocannabinoids have profound effects on synaptic and neuronal properties and, under certain some conditions, may improve higher brain functions. The most abundant endocannabinoid in the brain is 2-arachidonoylglycerol (2-AG). Similar to other lipid signaling molecules, levels of 2-AG are controlled by a balance of biosynthesis and degradation. The principal hydrolytic enzyme responsible for the degradation of 2-AG is monoacylglycerol lipase (MAGL). Consequently, genetic or pharmacological suppression of MAGL activity results in a robust increase of the brain levels of 2-AG and a concomitant reduction of arachidonic acid and downstream eicosanoid metabolites. Thus, inhibition of MAGL may simultaneously increase levels of 2-AG, resulting in activation of cannabinoid receptors, and reduce the release of eicosanoids, resulting in suppression of pro-inflammatory signaling in the nervous system. Recently, it was shown that inhibition of MAGL with JZL-184, the most selective and potent MAGL inhibitor, improved synaptic plasticity and memory in a mouse model of Alzheimer’s disease (AD). Furthermore, MAGL KO mice also exhibited increased synaptic plasticity and memory, suggesting that disruption of MAGL activity could positively affect higher brain functions. Finally, genetic or pharmacological inactivation of MAGL robustly suppressed accumulation of β-amyloid (Aβ) in a mouse AD model.
Down syndrome (DS) is a developmental disorder caused by triplication of chromosome 21. Mouse genetic models of DS carry an extra copy of genes homologous to those on human chromosome 21. One of the most widely used genetic models of DS, segmentally trisomic Ts65Dn mice, have three copies of most of the genes on mouse Chr 16 that are homologues of human Chr 21 genes, including the App gene. Ts65Dn mice exhibit abnormalities in brain structure, cognition, and behavior similar to those observed in people with DS. Thus, both people with DS and Ts65Dn mice have deficient hippocampus-dependent memory, working memory, exhibit multiple dendritic, synaptic, and neuronal abnormalities, and show the AD type pathology later in life.
Here we examined JZL-184 effects on the neural properties and behavior of aged Ts65Dn mice. We observed that chronic suppression of MAGL increased brain levels of 2-AG, restored spontaneous locomotor activity, and improved long-term memory and synaptic plasticity in Ts65Dn mice. In addition, JZL184-treatment decreased levels of Aβ40 and Aβ42 in both Ts65Dn and 2N mice. These results point to MAGL as a novel prospective therapeutic target for improving cognition and, possibly, ameliorating AD-type neuropathology during aging in individuals with DS.
(3) Conclusion–Inhibitor JZL-184
We observed here that chronic inhibition of MAGL with the selective inhibitor JZL-184 restored locomotor activity and improved long-term memory and synaptic plasticity in Ts65Dn mice, a model of DS. The JZL-184-treatment had no effect on the behavior and synaptic plasticity of normosomic control mice suggesting that suppression of MAGL activity is specifically efficacious in DS. This treatment also reduced levels of Aβ40 and Aβ42 but had no effect on the levels of full length App and BACE1 in both the Ts65Dn and 2N mice. Together, these results suggest that pharmacological targeting of MAGL may represent a novel and specific therapeutic approach for improving the cognitive impairments in DS.
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