Lehtonen M

References (8)

Title : Potent dual MAGL\/FAAH inhibitor AKU-005 engages endocannabinoids to diminish meningeal nociception implicated in migraine pain - Della Pietra_2023_J.Headache.Pain_24_38
Author(s) : Della Pietra A , Krivoshein G , Ivanov K , Giniatullina R , Jyrkkanen HK , Leinonen V , Lehtonen M , van den Maagdenberg A , Savinainen J , Giniatullin R
Ref : J Headache Pain , 24 :38 , 2023
Abstract : BACKGROUND: Engaging the endocannabinoid system through inhibition of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), degrading endocannabinoids (endoCBs) 2-arachidonoylglycerol (2-AG) and anandamide (AEA), was proposed as a promising approach to ameliorate migraine pain. However, the activity of MAGL and FAAH and action of endoCB on spiking activity of meningeal afferents, from which migraine pain originates, has not been explored thus far. Therefore, we here explored the analgesic effects of endoCB enhancement in rat and human meningeal tissues. METHODS: Both MAGL and FAAH activity and local 2-AG and AEA levels were measured by activity-based protein profiling (ABPP) and LC-MS/MS, respectively, in rat meninges obtained from hemiskulls of P38-P40 Wistar rats and human meninges from elderly patients undergoing non-migraine related neurosurgery. The action on endoCBs upon administration of novel dual MAGL/FAAH inhibitor AKU-005 on meningeal afferents excitability was tested by investigating paired KCl-induced spiking and validation with local (co-)application of either AEA or 2-AG. Finally, the specific TRPV1 agonist capsaicin and blocker capsazepine were tested. RESULTS: The basal level of 2-AG exceeded that of AEA in rat and human meninges. KCl-induced depolarization doubled the level of AEA. AKU-005 slightly increased spontaneous spiking activity whereas the dual MAGL/FAAH inhibitor significantly decreased excitation of nerve fibres induced by KCl. Similar inhibitory effects on meningeal afferents were observed with local applications of 2-AG or AEA. The action of AKU-005 was reversed by CB1 antagonist AM-251, implying CB1 receptor involvement in the anti-nociceptive effect. The inhibitory action of AEA was also reversed by AM-251, but not with the TRPV1 antagonist capsazepine. Data cluster analysis revealed that both AKU-005 and AEA largely increased long-term depression-like meningeal spiking activity upon paired KCl-induced spiking. CONCLUSIONS: In the meninges, high anti-nociceptive 2-AG levels can tonically counteract meningeal signalling, whereas AEA can be engaged on demand by local depolarization. AEA-mediated anti-nociceptive effects through CB1 receptors have therapeutic potential. Together with previously detected MAGL activity in trigeminal ganglia, dual MAGL/FAAH inhibitor AKU-005 appears promising as migraine treatment.
ESTHER : Della Pietra_2023_J.Headache.Pain_24_38
PubMedSearch : Della Pietra_2023_J.Headache.Pain_24_38
PubMedID: 37038131
Gene_locus related to this paper: human-MGLL

Title : In Vivo Characterization of the Ultrapotent Monoacylglycerol Lipase Inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)m ethanone (JJKK-048) - Aaltonen_2016_J.Pharmacol.Exp.Ther_359_62
Author(s) : Aaltonen N , Kedzierska E , Orzelska-Gorka J , Lehtonen M , Navia-Paldanius D , Jakupovic H , Savinainen JR , Nevalainen T , Laitinen JT , Parkkari T , Gynther M
Ref : Journal of Pharmacology & Experimental Therapeutics , 359 :62 , 2016
Abstract : Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders, and cancer. We have previously reported piperidine triazole urea, {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)m ethanone (JJKK-048), to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here, we characterize in vivo effects of JJKK-048. Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling revealed that JJKK-048 maintains good selectivity toward MAGL over other serine hydrolases. Our results are also the first to show that JJKK-048 promoted significant analgesia in a writhing test with a low dose that did not cause cannabimimetic side effects. At a high dose, JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hyperthermia, but not catalepsy.
ESTHER : Aaltonen_2016_J.Pharmacol.Exp.Ther_359_62
PubMedSearch : Aaltonen_2016_J.Pharmacol.Exp.Ther_359_62
PubMedID: 27451409

Title : Increased tonic cannabinoid CB1R activity and brain region-specific desensitization of CB1R Gi\/o signaling axis in mice with global genetic knockout of monoacylglycerol lipase - Navia-Paldanius_2015_Eur.J.Pharm.Sci_77_180
Author(s) : Navia-Paldanius D , Aaltonen N , Lehtonen M , Savinainen JR , Taschler U , Radner FP , Zimmermann R , Laitinen JT
Ref : Eur J Pharm Sci , 77 :180 , 2015
Abstract : In mammalian brain, monoacylglycerol lipase (MAGL) is the primary enzyme responsible for terminating signaling function of the endocannabinoid 2-arachidonoylglycerol (2-AG). Previous in vivo studies with mice indicate that both genetic and chronic pharmacological inactivation of MAGL result in 8-30-fold increase of 2-AG concentration in the brain, causing desensitization and downregulation of cannabinoid CB1 receptor (CB1R) activity, leading to functional and behavioral tolerance. However, direct evidence for reduced CB1R activity in the brain is lacking. In this study, we used functional autoradiography to assess basal and agonist-stimulated CB1R-dependent Gi/o protein activity in multiple brain regions of MAGL-KO mice in comparison to their wild-type (WT) littermates. In addition, the role of endogenous cannabinoids in basal CB1R signaling was assessed after comprehensive pharmacological blockade of 2-AG hydrolysis by determining the contents of endocannabinoids (eCBs) in WT and MAGL-KO brain tissues by LC/MS/MS technology. To show whether lack of MAGL cause compensatory alterations in the serine hydrolase activity, we compared serine hydrolase pattern of WT and MAGL-KO using activity-based protein profiling. Consistent with studies using chronic pharmacological MAGL inactivation in vivo, we observed a statistically significant decrease of CB1R-Gi/o signaling in most of the studied brain regions. In MAGL-KO brain sections, elevated 2-AG levels were mirrored to heightened basal CB1R-dependent Gi/o-activity, as well as, dampened agonist-evoked responses in several brain regions. The non-selective serine hydrolase inhibitor methylarachidonoylfluorophosphonate (MAFP) was able to significantly elevate 2-AG levels in brain sections of MAGL-KO mice, indicating that additional serine hydrolases possess 2-AG hydrolytic activity in MAGL-KO brain sections.
ESTHER : Navia-Paldanius_2015_Eur.J.Pharm.Sci_77_180
PubMedSearch : Navia-Paldanius_2015_Eur.J.Pharm.Sci_77_180
PubMedID: 26070239

Title : Discovery of Triterpenoids as Reversible Inhibitors of alpha\/beta-hydrolase Domain Containing 12 (ABHD12) - Parkkari_2014_PLoS.One_9_e98286
Author(s) : Parkkari T , Haavikko R , Laitinen T , Navia-Paldanius D , Rytilahti R , Vaara M , Lehtonen M , Alakurtti S , Yli-Kauhaluoma J , Nevalainen T , Savinainen JR , Laitinen JT
Ref : PLoS ONE , 9 :e98286 , 2014
Abstract : BACKGROUND: alpha/beta-hydrolase domain containing (ABHD)12 is a recently discovered serine hydrolase that acts in vivo as a lysophospholipase for lysophosphatidylserine. Dysfunctional ABHD12 has been linked to the rare neurodegenerative disorder called PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, cataract). In vitro, ABHD12 has been implicated in the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG). Further studies on ABHD12 function are hampered as no selective inhibitor have been identified to date. In contrast to the situation with the other endocannabinoid hydrolases, ABHD12 has remained a challenging target for inhibitor development as no crystal structures are available to facilitate drug design. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the unexpected discovery that certain triterpene-based structures inhibit human ABHD12 hydrolase activity in a reversible manner, the best compounds showing submicromolar potency. Based on structure activity relationship (SAR) data collected for 68 natural and synthetic triterpenoid structures, a pharmacophore model has been constructed. A pentacyclic triterpene backbone with carboxyl group at position 17, small hydrophobic substituent at the position 4, hydrogen bond donor or acceptor at position 3 accompanied with four axial methyl substituents was found crucial for ABHD12 inhibitor activity. Although the triterpenoids typically may have multiple protein targets, we witnessed unprecedented selectivity for ABHD12 among the metabolic serine hydrolases, as activity-based protein profiling of mouse brain membrane proteome indicated that the representative ABHD12 inhibitors did not inhibit other serine hydrolases, nor did they target cannabinoid receptors. CONCLUSIONS/SIGNIFICANCE: We have identified reversibly-acting triterpene-based inhibitors that show remarkable selectivity for ABHD12 over other metabolic serine hydrolases. Based on SAR data, we have constructed the first pharmacophore model of ABHD12 inhibitors. This model should pave the way for further discovery of novel lead structures for ABHD12 selective inhibitors.
ESTHER : Parkkari_2014_PLoS.One_9_e98286
PubMedSearch : Parkkari_2014_PLoS.One_9_e98286
PubMedID: 24879289
Gene_locus related to this paper: human-ABHD12

Title : Robust Hydrolysis of Prostaglandin Glycerol Esters by Human Monoacylglycerol Lipase (MAGL) - Savinainen_2014_Mol.Pharmacol_86_522
Author(s) : Savinainen JR , Kansanen E , Pantsar T , Navia-Paldanius D , Parkkari T , Lehtonen M , Laitinen T , Nevalainen T , Poso A , Levonen AL , Laitinen JT
Ref : Molecular Pharmacology , 86 :522 , 2014
Abstract : The primary route of inactivation of the endocannabinoid 2-arachidonoylglycerol in the central nervous system is through enzymatic hydrolysis, mainly carried out by monoacylglycerol lipase (MAGL), along with a small contribution by the alpha/beta-hydrolase domain (ABHD) proteins ABHD6 and ABHD12. Recent methodological progress allowing kinetic monitoring of glycerol liberation has facilitated substrate profiling of the human endocannabinoid hydrolases, and these studies have revealed that the three enzymes have distinct monoacylglycerol substrate and isomer preferences. Here, we have extended this substrate profiling to cover four prostaglandin glycerol esters, namely, 15-deoxy-Delta(12,14)-prostaglandin J2-2-glycerol (15d-PGJ2-G), PGD2-G, PGE2-G, and PGF2 alpha-G. We found that the three enzymes hydrolyzed the tested substrates, albeit with distinct rates and preferences. Although human ABHD12 (hABHD12) showed only marginal activity toward PGE2-G, hABHD6 preferentially hydrolyzed PGD2-G, and human MAGL (hMAGL) robustly hydrolyzed all four. This was particularly intriguing for MAGL activity toward 15d-PGJ2-G whose hydrolysis rate rivaled that of the best monoacylglycerol substrates. Molecular modeling studies combined with kinetic analysis supported favorable interaction with the hMAGL active site. Long and short MAGL isoforms shared a similar substrate profile, and hMAGL hydrolyzed 15d-PGJ2-G also in living cells. The ability of 15d-PGJ2-G to activate the canonical nuclear factor erythroid 2-related factor (Nrf2) signaling pathway used by 15d-PGJ2 was assessed, and these studies revealed for the first time that 15d-PGJ2 and 15d-PGJ2-G similarly activated Nrf2 signaling as well as transcription of target genes of this pathway. Our study challenges previous claims regarding the ability of MAGL to catalyze PG-G hydrolysis and extend the MAGL substrate profile beyond the classic monoacylglycerols.
ESTHER : Savinainen_2014_Mol.Pharmacol_86_522
PubMedSearch : Savinainen_2014_Mol.Pharmacol_86_522
PubMedID: 25140003
Gene_locus related to this paper: human-ABHD6 , human-ABHD12 , human-MGLL

Title : Brain regional cannabinoid CB1 receptor signalling and alternative enzymatic pathways for 2-arachidonoylglycerol generation in brain sections of diacylglycerol lipase deficient mice - Aaltonen_2014_Eur.J.Pharm.Sci_51_87
Author(s) : Aaltonen N , Riera Ribas C , Lehtonen M , Savinainen JR , Laitinen JT
Ref : Eur J Pharm Sci , 51 :87 , 2014
Abstract : Endocannabinoids are the endogenous ligands of the G protein-coupled cannabinoid receptors. The principal brain endocannabinoid, 2-arachidonoylglycerol (2-AG), is enzymatically produced by postsynaptic neurons and then activates presynaptic CB1 receptors in a retrograde manner. The primary pathway for 2-AG generation is believed to be conversion from the diacylglycerols (DAGs) by two sn-1-specific lipases, DAGLalpha and DAGLbeta. Previous studies with DAGL-deficient mice indicated that DAGLalpha is the major enzyme needed for retrograde synaptic 2-AG signalling. The current study investigated whether the CB1 receptor-mediated Gi/o protein activity is altered in brain cryosections of DAGL-deficient mice when compared to wild-type mice and whether the sn-1-specific DAGLs are able to generate 2-AG in brain cryosections. Functional autoradiography indicated that brain regional CB1 receptor-Gi/o-activity largely remained unaltered in DAGLalpha-knockout and DAGLbeta-knockout mice when compared to wild-type littermates. Following comprehensive pharmacological blockade of 2-AG hydrolysis, brain sections generated sufficient amounts of 2-AG to activate CB1 receptors throughout the regions endowed with these receptors. As demonstrated by LC/MS/MS, this pool of 2-AG was generated via tetrahydrolipstatin-sensitive enzymatic pathways distinct from DAGLalpha or DAGLbeta. We conclude that in addition to the sn-1-specific DAGLs, additional 2-AG generating enzymatic pathways are active in brain sections.
ESTHER : Aaltonen_2014_Eur.J.Pharm.Sci_51_87
PubMedSearch : Aaltonen_2014_Eur.J.Pharm.Sci_51_87
PubMedID: 24012970

Title : Piperazine and piperidine triazole ureas as ultrapotent and highly selective inhibitors of monoacylglycerol lipase - Aaltonen_2013_Chem.Biol_20_379
Author(s) : Aaltonen N , Savinainen JR , Ribas CR , Ronkko J , Kuusisto A , Korhonen J , Navia-Paldanius D , Hayrinen J , Takabe P , Kasnanen H , Pantsar T , Laitinen T , Lehtonen M , Pasonen-Seppanen S , Poso A , Nevalainen T , Laitinen JT
Ref : Chemical Biology , 20 :379 , 2013
Abstract : Monoacylglycerol lipase (MAGL) terminates the signaling function of the endocannabinoid, 2-arachidonoylglycerol (2-AG). During 2-AG hydrolysis, MAGL liberates arachidonic acid, feeding the principal substrate for the neuroinflammatory prostaglandins. In cancer cells, MAGL redirects lipid stores toward protumorigenic signaling lipids. Thus MAGL inhibitors may have great therapeutic potential. Although potent and increasingly selective MAGL inhibitors have been described, their number is still limited. Here, we have characterized piperazine and piperidine triazole ureas that combine the high potency attributable to the triazole leaving group together with the bulky aromatic benzodioxolyl moiety required for selectivity, culminating in compound JJKK-048 that potently (IC50 < 0.4 nM) inhibited human and rodent MAGL. JJKK-048 displayed low cross-reactivity with other endocannabinoid targets. Activity-based protein profiling of mouse brain and human melanoma cell proteomes suggested high specificity also among the metabolic serine hydrolases.
ESTHER : Aaltonen_2013_Chem.Biol_20_379
PubMedSearch : Aaltonen_2013_Chem.Biol_20_379
PubMedID: 23521796
Gene_locus related to this paper: human-MGLL

Title : Effects of memantine and donepezil on cortical and hippocampal acetylcholine levels and object recognition memory in rats - Ihalainen_2011_Neuropharmacol_61_891
Author(s) : Ihalainen J , Sarajarvi T , Rasmusson D , Kemppainen S , Keski-Rahkonen P , Lehtonen M , Banerjee PK , Semba K , Tanila H
Ref : Neuropharmacology , 61 :891 , 2011
Abstract : This preclinical study investigated the ability of memantine (MEM) to stimulate brain acetylcholine (ACh) release, potentially acting synergistically with donepezil (DON, an acetylcholinesterase inhibitor). Acute systemic administration of either MEM or DON to anesthetized rats caused dose-dependent increases of ACh levels in neocortex and hippocampus, and the combination of MEM (5 mg/kg) and DON (0.5 mg/kg) produced significantly greater increases than either drug alone. To determine whether ACh release correlated with cognitive improvement, rats with partial fimbria-fornix (FF) lesions were treated with acute or chronic MEM or DON. Acute MEM treatment significantly elevated baseline hippocampal ACh release but did not significantly improve task performance on a delayed non-match-to-sample (DNMS) task, whereas chronic MEM treatment significantly improved DNMS performance but only marginally elevated baseline ACh levels. Acute or chronic treatment with DON (in the presence of neostigmine to allow ACh collection) did not significantly improve DNMS performance or alter ACh release. In order to investigate the effect of adding MEM to ongoing DON therapy, lesioned rats pretreated with DON for 3 weeks were given a single intraperitoneal dose of MEM. MEM significantly elevated baseline hippocampal ACh levels, but did not significantly improve DNMS task scores compared to chronic DON-treated animals. These data indicate that MEM, in addition to acting as an NMDA receptor antagonist, can also augment ACh release; however, in this preclinical model, increased ACh levels did not directly correlate with improved cognitive performance.
ESTHER : Ihalainen_2011_Neuropharmacol_61_891
PubMedSearch : Ihalainen_2011_Neuropharmacol_61_891
PubMedID: 21704049