Endocannabinoid system enhancement for the treatment of sphingolipid storage disorders

The endocannabinoid system is composed of a class of unique lipidic mediators including 2-arachidonoyl glycerol (2-AG) and anandamide (N-arachidonoyl ethanolamine, AEA), the metabolic enzymes for their synthesis and degradation along with the two G protein-coupled cannabinoid receptors (CB₁ and CB₂). The system controls several aspects of the development and function of neurons, it also associated with synaptic communication in some pathophysiological events. In addition, the endocannabinoid system plays a significant role in anti-inflammatory, prohomeostatic and neuroprotective functions. These qualities have made researchers explore the therapeutic potential of endocannabinoid modulation in treating neurological disorders. Studies have shown that membrane lipids are relevant to endocannabinoid function, it is therefore important to understand their relation in details.

Acid sphingomyelinase deficiency (ASMD) is a neurological disorder that results in neurodegeneration, cellular accumulation of the sphingolipid sphingomyelin and early death. The infantile neurovisceral form of acid sphingomyelinase deficiency (ASMD also known as acute neuronopathic ASMD or Niemann–Pick type A) is fatal. Various studies have been conducted to identify therapeutic approaches that are beneficial for patients with this disorder; however, they have mostly been inadequate for the neuronopathic forms.

In a new research paper published in the Journal EMBO Molecular Medicine, Spanish scientists from the Centro Biologia Molecular Severo Ochoa (CSIC-UAM): Dr. Adrián Bartoll, Ana Toledano-Zaragoza and Dr. María Dolores Ledesma explored the therapeutic benefits of enhancing the endocannabinoid system in a mouse lacking the acid sphingomyelinase (ASM-KO) that mimics the neurovisceral form of ASMD. Their findings revealed a pathophysiological crosstalk between the endocannabinoid system and neuronal sphingomyelin and the therapeutic benefits of enhancing the endocannabinoid system in ASMD and other sphingolipid storage disorders such as Niemann Pick type C. The research was conducted in collaboration with Dr. Josefina Casas (IQAC-CSIC), Professor Manuel Guzmán (Complutense University) and Professor Edward Schuchman from the Icahn School of Medicine at Mount Sinai in the United State and supported by the patient association Wylder Nation Foundation.

CB₁ and CB₂ receptors mediate endocannabinoid signaling in the mammalian brain. Therefore, the authors first characterized the CB₁ receptor anomalies in the brains of an infantile neurovisceral ASMD patient and ASM-KO mice with a focus on the analysis of the cerebellum, because it is the most affected brain area in the disease. The levels of CB₂ mRNA and protein were unchanged between ASM-KO mice and the wild type littermates. In contrast, there was a reduction in the mRNA and protein levels of CB₁ in the cerebellum and other brain areas of the ASM-KO mice compared to wild type littermates. CB₁ protein reduction was also observed in neurons of an ASMD-affected patient.

The research team found that a reduction in the expression of CB₁ in ASM-KO neurons correlated with elevated levels of sphingomyelin and an increase in the delivery of CB₁ to lysosomes, leading to its degradation. They also noticed that sphingomyelin levels in cultured ASM-KO neurons were reduced by enhancing endocannabinoid signaling. CB₁ activation via the inhibition of the endocannabinoid -degrading enzyme fatty acid amide hydrolase in ASM-KO neurons led to the activation of neutral sphingomyelinase and degradation of sphingomyelin without any associated cell toxicity.

It was interesting to notice that chronic oral treatment with a fatty acid amide hydrolase inhibitor starting at early stages of the disease (6 weeks of age), improved the behavior of ASM-KO mice, increased neuronal survival, reduced brain sphingomyelin levels and inflammation and extended their lifespan. The authors also confirmed the safety profile for the treatment even in advanced stages of the disease in ASM-KO mice. The administration of fatty acid amide hydrolase inhibitor  was beneficial in cells and mice affected by Niemann–Pick disease type C (NPC), another sphingolipid storage disease, where CB1 receptor is also pathologically downregulated.

In nutshell, the authors showed for the first time the various impacts of the endocannabinoid system in neurovisceral ASMD and in NPC that can be viewed as both pathological and beneficial. Their findings provide further proof that endocannabinoid enhancing interventions are a suitable novel treatment option for fatal sphingolipid storage disorders.