Focal cerebral ischemia and traumatic brain injury induce an escalating amount of cell death because of harmful mediators diffusing
from the original lesion site. Evidence suggests that healthy cells
surrounding these lesions attempt to protect themselves by producing endocannabinoids (eCBs) and activating cannabinoid receptors, the molecular target for marijuana-derived compounds.
Indeed, activation of cannabinoid receptors reduces the production
and diffusion of harmful mediators. Here, we provide evidence
that an exception to this pattern is found in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple
sclerosis. We show that cell damage induced by EAE does not lead
to increase in eCBs, even though cannabinoid receptors are functional because synthetic cannabinoid agonists are known to confine EAE-induced lesions. This lack of eCB increase is likely due to
IFN-, which is released by primed T cells invading the CNS. We
show that IFN- disrupts the functionality of purinergic P2X7
receptors, a key step controlling eCB production by microglia, the
main source of eCBs in brain. Accordingly, induction of EAE in
P2X7/ mice results in even lower eCB levels and more pronounced cell damage than in wild-type mice. Our data suggest that
the high level of CNS IFN- associated with EAE disrupts eCBmediated neuroprotection while maintaining functional cannabinoid receptors, thus providing additional support for the use of
cannabinoid-based medicine to treat multiple sclerosis.
