CB2 activation during epileptogenesis recruits immunomodulatory monocytes and mitigates cognitive, affective and seizure outcomes

Temporal lobe epilepsy (TLE) is frequently associated with severe cognitive impairment and psychiatric comorbidities that are highly disabling and not targeted by anti-seizure medications, highlighting the need for therapies that target epileptogenesis rather than merely suppress seizures. Despite strong evidence implicating neuroinflammation in this process, anti-inflammatory approaches have not yielded such therapies yet. Infiltrating peripheral monocytes are widely viewed as detrimental amplifiers of post-status epilepticus (SE) inflammation, although emerging data suggest context-dependent protective roles. The cannabinoid receptor type 2 (CB2), highly expressed in myeloid cells, represents a potential immunomodulatory target linking leukocyte recruitment and inflammatory polarization. Using a juvenile rat model of TLE, we characterized hippocampal neuroinflammation and CB2 expression during epileptogenesis and evaluated the effects of transient CB2 activation with the selective agonist GP1a. SE induced a rapid but transient inflammatory response and robust recruitment of peripheral monocytes that persisted as anti-inflammatory monocyte-derived macrophages. CB2 activation did not suppress early cytokine induction but selectively enhanced recruitment of anti-inflammatory monocytes and modestly increased anti-inflammatory signaling. Importantly, transient CB2 stimulation preserved synaptic plasticity, improved cognitive performance, reduced anxiety-like behavior, and delayed seizure onset. These findings identify CB2-dependent modulation of peripheral myeloid cells as a potential disease-modifying axis in TLE.