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

Abstract

Background/Aims: Remote ischemic preconditioning (RIPC) has protective effects on spinal cord ischemia reperfusion (I/R) injury, but the potential mechanisms remain unclear. In our study, the effects and underlying mechanisms of RIPC on blood-spinal cord barrier (BSCB) breakdown following I/R injury were investigated. Methods: animals underwent intraperitoneal administration with cannabinoid-1 (CB1) receptor antagonist AM251, cannabinoid-2 (CB2) receptor antagonist AM630 or vehicle 15 minutes before three 3-minute occlusion-reperfusion cycles on the right femoral artery or a sham operation. 30 minutes after the preconditioning, aortic arch was exposed with or without 14-minute occlusion. Neurological function was assessed with Tarlov scoring system. The disruption of BSCB was assessed by measuring Evans Blue (EB) extravasation. The expression of tight junction protein occludin was determined by western blot analyses. The expression and localization of CB1 and CB2 receptors were assessed by western blot and immunofluorescence. Results: RIPC attenuated the motor dysfunction, BSCB disruption and downregulation of occludin after I/R injury, which were impaired by blocking CB1 and CB2 receptors. Moreover, RIPC upregulated the elevated perivascular expression of CB1 and CB2 receptors following I/R injury. Conclusions: These results indicated that RIPC, through activation and upregulation of CB1 and CB2 receptors, was involved in preserving the integrity of BSCB after spinal cord I/R injury.

Exogenous activation of cannabinoid-2 receptor modulates TLR4/MMP9 expression in a spinal cord ischemia reperfusion rat model

“…A similar report has also showed that CB2R agonists, given either before or 10 min after the beginning of ischemia, reduced the microglial activation, the area of infarction, and neurological symptoms [17], suggesting that early treatment with CB2R agonists may attenuate ischemic cerebral injury. In our previous study, we observed the disrupted BSCB at 4 h after reperfusion [12], which may aggravate injury, resulting in paraplegia. Treatment with a selective CB2R agonist 1 h post spinal cord contusion injury also revealed beneficial effects [16].…”

“…In the spinal cord, CB1R is expressed constitutively in neurons, and can be induced by reactive astrocytes; while CB2R is strongly expressed in response to cascading inflammation associated with ischemic episode, mainly in astrocytes and immune infiltrates [11]. Our previous work showed that CB1R and CB2R were associated with BSCB disruption during spinal cord I/R injury [12]. CB1R increases rapidly to peak within 2 h to 6 h after ischemia, and returns to baseline at 24 h postischemia.…”

Current Mechanistic Concepts in Ischemia and Reperfusion Injury

“…Local ischemia is caused by obstruction of blood flow to tissue, resulting in a limited supply of oxygen and nutrients, which if prolonged, can impair energy metabolism and cell death [99]. The recovery of blood loss (reperfusion) leads to the reintroduction of oxygen and the production of ROS, leading to cell death associated with inactivation [100, 101]. …”

Repeated Non-Invasive Limb Ischemic Preconditioning Confers Cardioprotection Through PKC-Ԑ/STAT3 Signaling in Diabetic Rats

“…IPC-mediated protection of one organ or tissue (even peripheral muscle) also protects distant organs/tissues (e.g. heart or spinal cord) from ischemic injury through a different signaling pathway [6, 7], and this phenomenon is termed remote ischemic preconditioning (RIPC) [8]. Interestingly, brief cycles of non-invasive limb ischemia and reperfusion (NLIP), a type of RIPC, has been proven to be cardioprotective in experimental settings which is easy to operate [9, 10].…”