Naja sputatrix Venom Preconditioning Attenuates Neuroinflammation in a Rat Model of Surgical Brain Injury via PLA2/5-LOX/LTB4 Cascade Activation

Abstract

Inflammatory preconditioning is a mechanism in which exposure to small doses of inflammatory stimuli prepares the body against future massive insult by activating endogenous protective responses. Phospholipase A2/5-lipoxygenase/leukotriene-B4 (PLA2/5-LOX/LTB4) axis is an important inflammatory signaling pathway. Naja sputatrix (Malayan spitting cobra) venom contains 15% secretory PLA2 of its dry weight. We investigated if Naja sputatrix venom preconditioning (VPC) reduces surgical brain injury (SBI)-induced neuroinflammation via activating PLA2/5-LOX/LTB4 cascade using a partial frontal lobe resection SBI rat model. Naja sputatrix venom sublethal dose was injected subcutaneously for 3 consecutive days prior to SBI. We observed that VPC reduced brain edema and improved neurological function 24 h and 72 h after SBI. The expression of pro-inflammatory mediators in peri-resection brain tissue was reduced with VPC. Administration of Manoalide, a PLA2 inhibitor or Zileuton, a 5-LOX inhibitor with VPC reversed the protective effects of VPC against neuroinflammation. The current VPC regime induced local skin inflammatory reaction limited to subcutaneous injection site and elicited no other toxic effects. Our findings suggest that VPC reduces neuroinflammation and improves outcomes after SBI by activating PLA2/5-LOX/LTB4 cascade. VPC may be beneficial to reduce post-operative neuroinflammatory complications after brain surgeries.

Modification of kynurenine pathway via inhibition of kynurenine hydroxylase attenuates surgical brain injury complications in a male rat model

“…In this study, we focused on understanding the contribution of kynurenine pathway to perisurgical site injury after SBI. Various cytokines and inflammatory mechanisms are activated following SBI (Sherchan et al, ; Wang et al, ), which can stimulate KMO and thereby upregulate the downstream release of the neurotoxic QUIN. We first measured the endogenous expression of QUIN and KYNA in the perisurgical brain tissue following SBI.…”

Intranasal wnt3a Attenuates Neuronal Apoptosis through Frz1/PIWIL1a/FOXM1 Pathway in MCAO Rats

“…This reduction in neuronal apoptotic proteins with wnt3a administration was associated with significant neurobehavior improvement in forelimb placement and recovery of modified Garcia scores to sham levels. Studies have shown that MCAO causes deleterious neurological effects on modified Garcia (Wang et al, 2017) and left forelimb placement (Senda et al, 2011), tests that correlate with cerebral infarction. We examined the neuropathological damage at 24 and 72 h after MCAO and found our model to create significant neurological deficits.…”

Surgically-induced brain injury: where are we now?

“…In the following sections, we expand on the concept of preconditioning and propose the use of venom-derived proteins as a preconditioning therapy for SBI. [35,44,45,67,68], it has often been noted that clinical translation is limited since many injuries occur spontaneously. In the last few decades, the potential of PC, especially for scheduled (or elective) surgeries, has become a real focus in hopes of developing an effective therapy.…”

“…Investigators have been able to give insight into the pathology, cellular mechanism of action, and where areas of therapeutic focus should be for treating SBI. Now, with evidence supporting the efficacy of PC [34,67], the need remains to investigate a translational therapy. Because of the recent discoveries of snake venom PC and a further understanding of the mechanism driving these protective effects, we have focused our attention on specific venom protein components which we believe can provide protective effects for edema and hemorrhage.…”

“…Venom activities including intravascular hemolysis, pulmonary congestion and edema, anticoagulation, and death are believed to be caused primarily by the PLA 2 isoforms. After Kim et al [45] and Wang et al [67,68] demonstrated that venoms with PLA 2 can attenuate brain edema and improve neurological outcomes, we became interested in investigating a pure PLA 2 therapy. Because of the complex nature of the venoms these investigators used, and also the presence of immunogenic proteins in these venoms, there is a need to study a PLA 2 -rich venom such as that of P. papuanus.…”