N-stearoyltyrosine protects primary cortical neurons against Aβ(1–40)-induced injury through inhibiting endocannabinoid degradation

Aims N-stearoyltyrosine (NsTyr) as an anandamide (AEA) analog has close relationships with AEA not only in structure but also in terms of biological actions of endocannabinoids. Since β-amyloid (Aβ)-induced primary neuronal injury involves the activation of the endocannabinoid systems (ECS), the protective effects of NsTyr against Aβ(1–40)-induced neuronal injury and the mechanism were studied systematically in this paper. Main methods Cortical neurons were incubated with Aβ(1–40) for 24h. NsTyr was added to indicated concentrations 30min prior to injury. Key findings The best effects of NsTyr on Aβ(1–40)-induced primary neuronal injury occurred at 10μM. The mechanism of NsTyr on neuroprotective effects against Aβ(1–40)-induced cellular death first involved anti-apoptosis resulting from the activation of cannabinoid receptors, then the pre-receptor regulation of AEA by the inhibition of endocannabinoid inactivation. These data demonstrated that the protective effects of NsTyr on Aβ(1–40)-induced primary neuronal injury resulted from the inhibition of fatty acid amide hydrolase (FAAH) (IC50=16.54nM) and blocked AEA uptake mediated by anandamide membrane transporter (AMT) (IC50=11.74nM). Significance The activation of ECS by inhibiting the degradation of AEA is an effective pharmacological approach to suppress Aβ-induced neuropathic injury. Our research could result in a more realistic alternative for AD treatment.