Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells.
BACKGROUND
Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice.


RESULTS
Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [(18) F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment.


CONCLUSIONS
JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.
MediCity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6 A, FI-20520, Turku, Finland. rea.pihlaja@utu.fi.
Rea
R
Pihlaja
MediCity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6 A, FI-20520, Turku, Finland. jatta.takkinen@utu.fi.
Jatta
J
Takkinen
Turku PET Centre, Radiopharmaceutical Chemistry Laboratory, University of Turku, Turku, Finland. olli.eskola@utu.fi.
Olli
O
Eskola
MediCity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6 A, FI-20520, Turku, Finland. jenni.vasara@utu.fi.
Jenni
J
Vasara
MediCity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6 A, FI-20520, Turku, Finland. francisco.lopez@utu.fi.
Francisco R
FR
López-Picón
MediCity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6 A, FI-20520, Turku, Finland. merja.haaparanta-solin@utu.fi.
Merja
M
Haaparanta-Solin
Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland. juha.rinne@tyks.fi.
Juha O
JO
Rinne
D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D052117:Benzodioxoles / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects*; D009573:Nitrites / Q000378:metabolism; D010880:Piperidines / Q000627:therapeutic use*
C491049:Aif1 protein, mouse; D016564:Amyloid beta-Protein Precursor; D052117:Benzodioxoles; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; C534333:JZL 184; D008840:Microfilament Proteins; D009573:Nitrites; D010880:Piperidines; D007371:Interferon-gamma; D008994:Monoacylglycerol Lipases