Different studies have demonstrated that
inflammation and alterations in
glutamate neurotransmission are two events contributing to the pathophysiology of neurodegenerative or
neurological disorders. There are evidences that N-arachidonoylphenolamine (
AM404), a
cannabinoid system modulator and
paracetamol metabolite, modulates
inflammation and exerts
neuroprotective effects on Huntington's (HD) and Parkinson's diseases (PD), and
ischemia. However, the effects of
AM404 on the production of inflammatory mediators and excitotoxicity in brain tissue stimulated with
N-methyl-D-aspartic acid (
NMDA) are not elucidated. In this present study, we investigated the effects of
AM404 on the production of inflammatory mediators and neuronal cell death induced by
NMDA in organotypic hippocampal slices cultures (OHSC) using qPCR, western blot (WB), and immunohistochemistry. Moreover, to comprehend the mechanism of excitotoxicity, we evaluated the effects of
AM404 on
glutamate release in hippocampal synaptosomes and the
NMDA-induced
calcium responses in acute hippocampal slices. Our results showed that
AM404 led to a significant decrease in cell death induced by
NMDA, through a mechanism possibly involving the reduction of
glutamate release and the
calcium ions responses. Furthermore, it decreased the expression of the
interleukin (IL)-1β. This study provides new significant insights about the anti-inflammatory and neuroprotection effects of
AM404 on
NMDA-induced excitotoxicity. To understand the effects of
AM404 in these processes might contribute to the therapeutic potential of
AM404 in diseases with involvement of
neuroinflammation and neurodegeneration and might lead to a possible future treatment of
neurodegenerative diseases.