Table 3.

Synthetic cannabinoids in TBI models

Treatment	Dose	Route	Frequency	Model	Species	Results	References
Arachidonyl-2′-chloroethylamide (ACEA) (CB1R agonist)	1 mg/kg	i.p.	Within 10 min of injury and daily for 6 days (seven doses in total)	CCI (with craniotomy)	Sprague–Dawley rats, males	Treatment attenuated CCI-induced deficits in novel object recognition and Morris water maze performance. Treatment did not alter lesion size after CCI	[141]
HU-910 and HU-914 (CB2R agonists)	0.1–10 mg/kg HU-910 5–10 mg/kg HU-914	i.p.	Single dose 1 h post-injury	Weight-drop mTBI	Sabra mice, males and CB2 KO mice Sprague–Dawley rats, males	Treatment improved NSS over 28 days; inhibited TNFa; increased synaptogenesis; and resulted in partial recovery of corticospinal tract	[130]
JWH-133 or 0-1966 (CB2R agonists) and SR144528 (CB2R antagonist)	1 mg/kg 5 mg/kg 5 mg/kg	i.p.	2 or 18 h post-injury	CCI (with craniotomy)	Wild-type and CB2 KO mice	Treatment reduced sodium fluorescein uptake in CB2 agonist-treated WT mice but not CB2 KO mice; and CB2 KO mice had enhanced TNFa levels	[131]
JWH-133 (CB2R agonist) ± SR144528 (CB2R antagonist)	1.5 mg/kg 3 mg/kg	i.p.	1 h post-injury	CCI (with craniotomy)	Sprague–Dawley rats, males	JWH-133 treatment increased M2 microglia/macrophage polarization via PERK pathway; decreased white matter injury and demyelination; reversed tissue loss; prevented loss of OPCs and OL; restored myelin G-ratio; resulted in fewer unmyelinated axons; restored fractional anisotropy; and improved cerebral blood flow. JWH-133 treatment reduced anxiety-like behavior and improved spatial memory (MWM). Treatment effects were blocked by SR144528	[135]
GP1a (CB2R agonist) ± AM630 (CB2R antagonist)	1–5 mg/kg 5 mg/kg	i.p.	10 min post-injury	CCI (with craniotomy)	C57BL/6 mice, males; and CD1 mice, males	GP1a treatment reduced inflammation; reduced neurovascular injury, biased macrophages to M2; reduced edema; enhanced cerebral blood flow; improved beamwalk and RotaRod performance; and reduced anxiety-like behavior (OFT). AM630 treatment was not beneficial	[136]
0-1966 (CB2R agonist)	5 mg/kg	i.p.	2 or 18 h post-injury for 1 day endpoint, or 2 and 24 h post-injury for 2 day endpoint, and 1, 24, 48, and 72 h post-injury for the 7 day endpoint	CCI (with craniotomy)	C57BL/6 mice, males	Sodium fluorescein uptake peaked 1 day post-CCI. 0-1966 treatment reduced or ameliorated CCI-induced effects, such as increased fluoro-jade labeling, macrophage/microglia counts, and motor impairment	[132]
0-1966 (CB2R agonist)	5 mg/kg	i.p.	1 and 24 h post-injury	CCI (with craniotomy)	C57BL/6 mice, males	CCI impaired motor and exploratory activity. CCI increased cortical edema, substance P, and macrophage/microglia count. 0-1966 treatment reduced all CCI-induced effects	[133]
SMM-189 (CB2R inverse agonist)	6 mg/kg	i.p.	Once daily from day 0 (day of injury) to day 13 (14 doses total)	Blast TBI, blast pressure 50–60 psi above atmospheric pressure applied to left side	C57BL6 mice or EYFP-reporter mice, males	Treatment improved contrast sensitivity; reduced the elevated number of axon bulbs in the optic nerve; reduced axon loss in the left optic nerve; and reduced microglia and GFAP labelling in left optic nerve	[140]
SMM-189 (CB2R inverse agonist)	6 mg/kg	i.p.	Once daily from day 0 (day of injury) to day 13 (14 doses total)	Focal cranial blast injury (mTBI), blast pressure 50–60 psi above atmospheric pressure applied to left side	C57BL6 mice, males	Local field potential coherence was increased in the prefrontal cortex and somatosensory cortex after injury. Treatment restored PFC coherence to control levels. Spike frequency in CA1 was decreased after injury but restored by treatment	[139]
Raloxifene (CB2R inverse agonist and selective estrogen receptor modulator)	5 or 10 mg/kg	i.p.	Once daily from day 0 (day of injury) to day 13 (14 doses total)	Ocular blast injury, blast pressure 50–60 psi above atmospheric pressure applied to left side	C57BL6 mice, males	Treatment improved contrast sensitivity and visual acuity; improved light aversion; rescued ON axon loss in the left eye; improved ipRGC size; and increased melanopsin levels	[137]
Raloxifene (CB2R inverse agonist and selective estrogen receptor modulator)	5 or 10 mg/kg	i.p.	1× daily from day 0 (day of injury) for 4 or 15 daily doses	Single or repeated (5×) ocular blast injury, blast pressure 25 psi above atmospheric pressure	C57BL6 mice, males	Treatment prevented injury-induced light aversion; reduced optic nerve axon loss; improved contrast sensitivity and visual acuity; reduced retinal pathology and optic nerve axon pathology; and biased towards M2 microglia	[138]