Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling

Abstract

Acid sphingomyelinase deficiency (ASMD) leads to cellular accumulation of sphingomyelin (SM), neurodegeneration, and early death. Here, we describe the downregulation of the endocannabinoid (eCB) system in neurons of ASM knockout (ASM‐KO) mice and a ASMD patient. High SM reduced expression of the eCB receptor CB1 in neuronal processes and induced its accumulation in lysosomes. Activation of CB1 receptor signaling, through inhibition of the eCB‐degrading enzyme fatty acid amide hydrolase (FAAH), reduced SM levels in ASM‐KO neurons. Oral treatment of ASM‐KO mice with a FAAH inhibitor prevented SM buildup; alleviated inflammation, neurodegeneration, and behavioral alterations; and extended lifespan. This treatment showed benefits even after a single administration at advanced disease stages. We also found CB1 receptor downregulation in neurons of a mouse model and a patient of another sphingolipid storage disorder, Niemann–Pick disease type C (NPC). We showed the efficacy of FAAH inhibition to reduce SM and cholesterol levels in NPC patient‐derived cells and in the brain of a NPC mouse model. Our findings reveal a pathophysiological crosstalk between neuronal SM and the eCB system and offer a new treatment for ASMD and other sphingolipidoses.

Deletion of fatty acid amide hydrolase reduces lyso-sulfatide levels but exacerbates metachromatic leukodystrophy in mice

“…Aggravation of the disease phenotype is also difficult to explain in view of the known anti-inflammatory and neuroprotective effects exerted by inhibition of FAAH activity in many animal models of neurological diseases ( 31 ). Only recently, it has been shown, for example, that oral treatment of sphingomyelinase-deficient mice (model of the lysosomal storage disease Niemann–Pick type A/B) with FAAH inhibitors alleviated neuroinflammation, retarded neurodegeneration, improved behavioral alterations, and extended life span ( 32 ). To find a possible explanation for the severe phenotype of FAAH-deficient MLD mice, we quantified AEA and cytokines in total brain.…”

The Multiple Roles of Sphingomyelin in Parkinson’s Disease

“…In the neurons of aSMase KO mice, there is a pathological downregulation of the endocannabinoid system and inhibitors of the endocannabinoid-degrading enzyme fatty acid amide hydrolase reduce SM storage by limiting neurodegeneration [ 53 ].…”

Can antidepressants unlock prescription of rimonabant in the fight against COVID-19?

“…Relevance of this mechanism was recently confirmed by the observation that other ASmase functional inhibitors (antihistamines, antipsychotics, calcium channel blockers, mucolytics) also protect from severe forms of COVID-19 [ 7 ]. However, a close relationship between sphingomyelin metabolism and CB1R was recently reported in a study showing that sphingomyelin accumulation subsequent to ASmase deficiency promoted disappearance of membrane CB1R through internalization and lysosomal degradation [ 8 ]. On the other hand, chronic activation of CB1R (induced by inhibiting enzymatic degradation of the CB1R ligand anandamide) dampened sphingomyelin excessive storage in ASmase-knock-out mice [ 8 ].…”

“…However, a close relationship between sphingomyelin metabolism and CB1R was recently reported in a study showing that sphingomyelin accumulation subsequent to ASmase deficiency promoted disappearance of membrane CB1R through internalization and lysosomal degradation [ 8 ]. On the other hand, chronic activation of CB1R (induced by inhibiting enzymatic degradation of the CB1R ligand anandamide) dampened sphingomyelin excessive storage in ASmase-knock-out mice [ 8 ]. Since inhibition of ASmase results in some accumulation of sphingomyelin [ 6 ], such a crosstalk between the two metabolisms (sphingomyelin-ceramide and endocannabinoids, respectively) could cast some doubts about the advantage of combining rimonabant with an antidepressant.…”

“…Since inhibition of ASmase results in some accumulation of sphingomyelin [ 6 ], such a crosstalk between the two metabolisms (sphingomyelin-ceramide and endocannabinoids, respectively) could cast some doubts about the advantage of combining rimonabant with an antidepressant. However, sphingomyelin accumulation in hippocampal Golgi or endoplasmic reticulum fractions of mice treated with amitriptyline remained 7- to 11-fold lower, respectively, than the massive increase observed in ASmase-deficient mice [ 8 ]. To the best of our knowledge, there is no report that antidepressants could induce the dramatic changes observed in ASmase deficiency characterizing Niemann-Pick disease type A.…”