Early Endogenous Activation of CB1 and CB2 Receptors after Spinal Cord Injury Is a Protective Response Involved in Spontaneous Recovery

Abstract

Spinal cord injury (SCI) induces a cascade of processes that may further expand the damage (secondary injury) or, alternatively, may be part of a safeguard response. Here we show that after a moderate-severe contusive SCI in rats there is a significant and very early increase in the spinal cord content of the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (anandamide, AEA). Since 2-AG and AEA act through CB1 and CB2 cannabinoid receptors, we administered at 20 minutes after lesion a single injection of their respective antagonists AM281 and AM630 alone or in combination to block the effects of this early endocannabinoid accumulation. We observed that AM281, AM630 or AM281 plus AM630 administration impairs the spontaneous motor recovery of rats according to the Basso-Beattie-Bresnahan (BBB) locomotor scale. However, blockade of CB1, CB2 or both receptors produced different effects at the histopathological level. Thus, AM630 administration results at 90 days after lesion in increased MHC-II expression by spinal cord microglia/monocytes and reduced number of serotoninergic fibres in lumbar spinal cord (below the lesion). AM281 exerted the same effects but also increased oedema volume estimated by MRI. Co-administration of AM281 and AM630 produced the effects observed with the administration of either AM281 or AM630 and also reduced white matter and myelin preservation and enhanced microgliosis in the epicentre. Overall, our results suggest that the endocannabinoids acting through CB1 and CB2 receptors are part of an early neuroprotective response triggered after SCI that is involved in the spontaneous recovery after an incomplete lesion.

Detrimental effects of 2-arachidonoylglycerol on whole blood platelet aggregation and on cerebral blood flow after a focal ischemic insult in rats

“…Sham-operated animals underwent MCAO surgery without insertion of the filament. Animals were maintained for up to 4 h after the onset of MCAO, as neuroprotective effects of 2-AG have been shown to be mediated by a reduction in the early (1-4 h) inflammatory response (48) or early endogenous activation of CB receptors (2). Therefore, the 4 h time point not only allows cardiovascular and cerebrovascular responses to be monitored continuously during MCAO but also allows insights into the effects of 2-AG on the evolution of neuronal injury and the early microglial response.…”

“…2-AG can act as a full agonist at both cannabinoid (CB)1 and CB2 receptors and can be rapidly metabolized in vivo to arachidonic acid and prostaglandin glycerol ester through enzyme pathways including monoacylglycerol lipase (MAGL) (16) and cyclooxygenase (34). Cyclooxygenase can further metabolize arachidonic acid to PGG 2 and PGH 2 , which in turn may be converted to thromboxane, prostacyclin, and other prostaglandins, all of which have important physiological and pathological actions. 2-AG can be produced by many cells, including endothelial cells and platelets (47).…”

Progesterone Reduces Secondary Damage, Preserves White Matter, and Improves Locomotor Outcome after Spinal Cord Contusion

“…23,24 Briefly, animals were anesthetized with an intraperitoneal injection of sodium pentobarbital (45 mg/kg, Normon Veterinary Division, Madrid, Spain) and Xilagesic (2% xylazine, 10 mg/kg, Calier, Barcelona, Spain). Once the absence of reflexes had been checked, the rats were injected with a low dose of atropine (50 lg/kg body weight; Brown Medical, Barcelona, Spain) to reduce salivary and bronchial secretions and to avoid the induction of bradycardia and possible cardiac arrest by the surgery or xylazine.…”

Remote Ischemia Preconditioning Attenuates Blood-Spinal Cord Barrier Breakdown in Rats Undergoing Spinal Cord Ischemia Reperfusion Injury: Associated with Activation and Upregulation of CB1 and CB2 Receptors

“…Endocannabinoids are released rapidly following either brain or spinal cord injury [30, 31]. The CB1 and CB2 receptors expression in the brain are elevated after cerebral ischemia.…”