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P.1.g.045 Neuroprotective effect of the monoacylglycerol lipase inhibitor JZL184 in a parkinsonian mouse model
P.1.g. Basic and clinical neuroscience − Neuropharmacology with postpartum depression [1,2]. Here we used blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to investigate whether a gonadotropin releasing hormone agonist (GnRHa)-induced downregulation of sex-hormones has an influence on emotional processing. Methods: In this double-blinded, placebo-controlled study, healthy women were examined twice with whole-brain fMRI at 3T. During fMRI, participants performed a gender labelling task of faces expressing anger, fear, happiness or no emotion. Baseline fMRI was performed in the midfollicular phase (cycle day 7±2). Participants received intervention with GnRHa (3.6 mg Goserelin implant, n = 30) or placebo (saline injection, n = 28) in the midluteal phase of a natural cycle (cycle day 23±3), and follow-up was performed 16±3 days after. Two subjects were excluded from the placebo group due to faulty cycle timing and failure to comply with the task, respectively. Depressive symptoms were measured with the Hamilton Depression Scale (HDS) pre and post intervention. Analyses were conducted in SPM8 with a cluster filter of five voxels and significance filter of 0.001 uncorrected. Small volume correction (SVC) was applied for the amygdala. Results: As expected, Goserelin initially increased, and subsequently reduced, estradiol levels (0.18±0.09 to 0.06±0.04nmol/L) and led to an increase in HDS scores relative to placebo. There was no main effect of the GnRHa on the neural response to angry or fearful faces. However, the GnRHa-induced decline in estradiol levels and increase in HDS correlated significantly with a changed neural response of the amygdala to angry but not fearful faces (compared to neutral). Thus, amygdala showed a larger decrease in activity in women with (i) a larger reduction in estradiol (pSVC < 0.05, z = 4.1, Spearman correlation with extracted peak (−20, 4, −22) values: 0.56, p = 0.001, R2 = 0.46), and (ii) a larger increase in HDS (pSVC < 0.05, z = 3.6, Spearman correlation with extracted peak (34, −2, −28) values: −0.59, p = 0.001, R2 = 0.34). Controlling for HDS did not affect the influence of estradiol on amygdala activity and vice versa. There was no interaction between estradiol and HDS on the change in amygdala activity as reflected by the regional BOLD signal. In addition, there was a main effect of GnRHa treatment on the processing of happy faces in a region encompassing the insula and putamen (pwhole−brain = 0.01, (30, −6, 8), z = 4.0). The effect was driven by an increased activity post-intervention in the GnRHa group and a decrease in the placebo group. Activity in this region did not display a significant correlation with changes in estradiol levels or HDS in the GnRHa-group. Conclusion: The results demonstrate that sex-hormone downregulation blunts the reactivity of amygdala to angry faces in a dose-dependent manner. Notably, this blunting was positively coupled to the development of subclinical depressive symptoms and thereby implicates amygdala function in the mechanisms by which sex-hormone fluctuations may increase the risk for depression. References [1] Groenewold NA, Opmeer EM, de Jonge P, Aleman A, Costafreda SG., 2012 Emotional valence modulates brain functional abnormalities in depression: evidence from a meta-analysis of fMRI studies. Neurosci Biobehav Rev. 37(2), 152−63. [2] Moses-Kolko EL, Perlman SB, Wisner KL, James J, Saul AT, Phillips ML., 2010 Abnormally reduced dorsomedial prefrontal cortical activity and effective connectivity with amygdala in response to negative emotional faces in postpartum depression. Am J Psychiatry. 167(11): 1373−80.
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P.1.g.045 Neuroprotective effect of the monoacylglycerol lipase inhibitor JZL184 in a parkinsonian mouse model M. Celorrio1 ° , D. Fern´andez-Su´arez1 , R. Franco1 , M.S. Aymerich2 1 Center for Applied Medical Research, Neurosciences, Pamplona, Spain; 2 University of Navarra, Biochemistry and Genetics, Pamplona, Spain The elements of the endocannabinoid system, receptors, ligands and enzymes that control endocannabinoid synthesis and degradation, are particularly abundant in basal ganglia. The motor effects resulting from the activation or blockade of cannabinoid signaling are related to the ability of the system to modulate the activity of the main neurotransmitters involved in basal ganglia function: glutamate, GABA and dopamine. The endocannabinoid system is unbalanced in Parkinson’s disease in which: i) CB1 receptors are up-regulated in the striatum after dopaminergic denervation, both in experimental animals and in humans, ii) differential changes in endocannabinoid levels are found in different nuclei of basal ganglia from animal models of Parkinson’s disease and iii) anandamide levels are increased in the cerebrospinal fluid of patients with Parkinson’s disease. In general, the endocannabinoid system is up-regulated in Parkinson’s disease, although it is not clear whether these changes contribute to, or result from, the disease process. The potential use of drugs interfering with CB1 receptor activity remains controversial. The aim of the present work was to study the effect of the inhibition of monoacylglycerol lipase (MAGL) in a Parkinson’s disease model. MAGL is the enzyme that degrades 2-arachinoyl-glycerol (2-AG) and the main regulator of 2-AG levels in the brain. 2-AG is the most abundant endocannabinoid in the brain and an agonist of CB1 and CB2 receptors. A parkinsonian mouse model with partial and stable dopaminergic degeneration was chosen. A dopaminergic lesion was bilaterally made in mice by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg) and probenecid (250 mg/kg) twice a week during 5 weeks. During the same period, a subset of MPTP-lesioned mice received an intraperitoneal injection of the irreversible MAGL inhibitor, JZL184 (8 mg/kg) five times a week. At the end of the treatment, the motor behavior was analyzed by the rotarod and the pole test, showing a significant motor recovery in parkinsonian animals treated with JZL184. In the JZL184-treated animals tyrosine hydroxylase immunohistochemistry and Western blot analysis demonstrated a significant increase in the number of dopaminergic neurons in the sustantia nigra and their terminals in the striatum. The haloperidol-induced catalepsy test failed to show any symptomatic effect of JZL184, indicating that the improvement in motor behavior was due to neuroprotection. At the doses used, JZL184 failed to elicit any of the cannabinoid-like effects, as measured by the so-called cannabinoid tetrad that includes the measurement of body temperature, and the tail-flick, the catalepsy and the open field tests. These results indicate that JZL184 is neuroprotective in chronic Parkinson’s disease models and that JZL184 treatment does not induce some of the undesirable side effects of cannabinoid receptor agonism. In conclusion, inhibitors of MAGL such as JZL184 are able to improve the MPTP-induced parkinsonism not by alleviating the symptoms but by inducing neuroprotection of the nigrostriatal pathway.
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P.1.g.045 Neuroprotective effect of the monoacylglycerol lipase inhibitor JZL184 in a parkinsonian mouse model M. Celorrio1 ° , D. Fern´andez-Su´arez1 , R. Franco1 , M.S. Aymerich2 1 Center for Applied Medical Research, Neurosciences, Pamplona, Spain; 2 University of Navarra, Biochemistry and Genetics, Pamplona, Spain The elements of the endocannabinoid system, receptors, ligands and enzymes that control endocannabinoid synthesis and degradation, are particularly abundant in basal ganglia. The motor effects resulting from the activation or blockade of cannabinoid signaling are related to the ability of the system to modulate the activity of the main neurotransmitters involved in basal ganglia function: glutamate, GABA and dopamine. The endocannabinoid system is unbalanced in Parkinson’s disease in which: i) CB1 receptors are up-regulated in the striatum after dopaminergic denervation, both in experimental animals and in humans, ii) differential changes in endocannabinoid levels are found in different nuclei of basal ganglia from animal models of Parkinson’s disease and iii) anandamide levels are increased in the cerebrospinal fluid of patients with Parkinson’s disease. In general, the endocannabinoid system is up-regulated in Parkinson’s disease, although it is not clear whether these changes contribute to, or result from, the disease process. The potential use of drugs interfering with CB1 receptor activity remains controversial. The aim of the present work was to study the effect of the inhibition of monoacylglycerol lipase (MAGL) in a Parkinson’s disease model. MAGL is the enzyme that degrades 2-arachinoyl-glycerol (2-AG) and the main regulator of 2-AG levels in the brain. 2-AG is the most abundant endocannabinoid in the brain and an agonist of CB1 and CB2 receptors. A parkinsonian mouse model with partial and stable dopaminergic degeneration was chosen. A dopaminergic lesion was bilaterally made in mice by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg) and probenecid (250 mg/kg) twice a week during 5 weeks. During the same period, a subset of MPTP-lesioned mice received an intraperitoneal injection of the irreversible MAGL inhibitor, JZL184 (8 mg/kg) five times a week. At the end of the treatment, the motor behavior was analyzed by the rotarod and the pole test, showing a significant motor recovery in parkinsonian animals treated with JZL184. In the JZL184-treated animals tyrosine hydroxylase immunohistochemistry and Western blot analysis demonstrated a significant increase in the number of dopaminergic neurons in the sustantia nigra and their terminals in the striatum. The haloperidol-induced catalepsy test failed to show any symptomatic effect of JZL184, indicating that the improvement in motor behavior was due to neuroprotection. At the doses used, JZL184 failed to elicit any of the cannabinoid-like effects, as measured by the so-called cannabinoid tetrad that includes the measurement of body temperature, and the tail-flick, the catalepsy and the open field tests. These results indicate that JZL184 is neuroprotective in chronic Parkinson’s disease models and that JZL184 treatment does not induce some of the undesirable side effects of cannabinoid receptor agonism. In conclusion, inhibitors of MAGL such as JZL184 are able to improve the MPTP-induced parkinsonism not by alleviating the symptoms but by inducing neuroprotection of the nigrostriatal pathway.