Analgesic Activity of Synaptamide in a Rat Sciatic Nerve Chronic Constriction Injury Model

Abstract

At present, there is a growing interest in the study of the neurotropic activity of polyunsaturated fatty acid ethanolamides (N-acylethanolamines). N-docosahexaenoylethanolamine (DHEA), or synaptamide, an endogenous metabolite of docosahexaenoic acid, is a promising compound with anti-inflammatory activity. The results of this study demonstrate that synaptamide, when administered subcutaneously (4 mg/kg/day, 35 days), promotes a decrease in cold allodynia and mechanical hyperalgesia in a rat sciatic nerve chronic constriction injury (CCI) model. After CCI, synaptamide treatment enhanced the remyelination process in the site of sciatic nerve injury (33.4 ± 1.1% in the CCI+Syn group, compared to 28.4 ± 0.9% in the CCI group). Further, synaptamide suppressed the CCI-induced increase in the activity of microglia (13.1 ± 0.5% in CCI+Syn, compared to 15.3 ± 0.7% in the CCI group) and the number of nitric oxide synthase-positive neurons (58,307 ± 5,206 cells/mm<sup>3</sup> in CCI+Syn, compared to 80,288 ± 4,287 cells/mm<sup>3</sup> in the CCI group) in the dorsal horns of the spinal cord, and also reduced the concentration of interleukin 1 beta in the spinal cord (169.3 ± 4 pg/mg of protein in CCI+Syn, compared to 236.9 ± 9.3 pg/mg of protein in CCI group) 35 days after surgery. Synaptamide treatment resulted in decrease of reactive astrogliosis in the spinal cord dorsal horns to 20.8 ± 1.3%, which occurred simultaneously with a decrease in the substance P (SP) level (9.8 ± 0.5%) compared to vehicle-treated animals (30.2 ± 2.2% and 13.4 ± 0.9% of astroglia and SP staining area, respectively). In addition, synaptamide increased superoxide dismutase activity up to 68.6 ± 0.8% (control 50.6 ± 0.9%) in astrocyte culture. Thus, synaptamide provides anti-inflammatory and neuroprotective effects in both peripheral and central nervous system after sciatic nerve injury.

Synaptamide Modulates Astroglial Activity in Mild Traumatic Brain Injury

“…The presented data indicate an endogenous SOD concentration increase in 24 h after synaptamide administration in both Sham-operated and injured animals. This is consistent with the previous data obtained in the primary culture of astrocytes with the addition of synaptamide at a concentration of 10 μM [ 49 ]. However, in “mTBI” group, the growth in SOD activity is observed one week after the surgery, when neuroinflammation was most pronounced [ 14 ].…”

Anti-Inflammatory Activity of Synaptamide in the Peripheral Nervous System in a Model of Sciatic Nerve Injury

“…Synaptamide, the compound used in the current study, is another endogenous metabolite of DHA that can promote neurite- and synaptogenesis in neuronal cell cultures [ 15 , 16 , 17 , 18 ] and inhibit the release of proinflammatory cytokines in microglial cell cultures after lipopolysaccharide (LPS) treatment [ 19 , 20 ]. We have previously discovered that in neuropathic pain conditions, synaptamide treatment results in less pronounced pain-like behavior [ 24 , 25 , 26 ], reduces inflammation in the CNS [ 24 , 26 ], stabilizes neurogenesis in the hippocampus [ 24 ], and increases the production of N-acylethanolamines in plasma and the brain [ 25 ]. In our current study, we examine the effects of synaptamide treatment on the peripheral nervous system after chronic constriction injury of the sciatic nerve.…”

“…We have previously discovered that synaptamide treatment after the chronic constriction injury of the sciatic nerve affects the neuropathic pain development in rats, resulting in significantly less pronounced pain-like behavior [ 24 , 25 , 26 ], including a decrease in cold allodynia [ 25 , 26 ], as well as thermal [ 24 ] and mechanical hyperalgesia [ 26 ]. Furthermore, daily synaptamide administration prevents increased anxiety, and the impairment of locomotor activity, working, and long-term memory, caused by neuropathic pain syndrome [ 24 , 25 ].…”

“…Furthermore, daily synaptamide administration prevents increased anxiety, and the impairment of locomotor activity, working, and long-term memory, caused by neuropathic pain syndrome [ 24 , 25 ]. Synaptamide administration for 35 days after sciatic nerve injury reduces inflammation in the lumbar spinal cord [ 26 ] and the hippocampus [ 24 ] by decreasing microglia activity and proinflammatory cytokine concentrations. Synaptamide also improves neurogenesis in the dentate gyrus subgranular zone of the hippocampus 14- and 35-days post-injury [ 24 , 25 ].…”

“…Furthermore, synaptamide increases the concentration of N-acylethanolamines in plasma and the brain, in particular, the levels of oleoylethanolamide, palmitoylethanolamide, and arachidonylethanolamide [ 24 , 25 ]. Moreover, synaptamide administration results in the upregulation of superoxide dismutase (SOD) activity in microglia and astroglia cell cultures, thus improving the antioxidant activity and preventing peroxidative stress reactions [ 20 , 26 ]. The systemic anti-inflammatory and antioxidant properties of synaptamide are well-established features in the central nervous system (CNS); however, to date, the effects of synaptamide treatment on the peripheral nervous system have not been studied.…”