Modulation of Hippocampal Astroglial Activity by Synaptamide in Rats with Neuropathic Pain

Abstract

The present study demonstrates that synaptamide (N-docosahexaenoylethanolamine), an endogenous metabolite of docosahexaenoic acid, when administered subcutaneously (4 mg/kg/day, 14 days), exhibits analgesic activity and promotes cognitive recovery in the rat sciatic nerve chronic constriction injury (CCI) model. We analyzed the dynamics of GFAP-positive astroglia and S100β-positive astroglia activity, the expression of nerve growth factor (NGF), and two subunits of the NMDA receptor (NMDAR1 and NMDAR2A) in the hippocampi of the experimental animals. Hippocampal neurogenesis was evaluated by immunohistochemical detection of DCX. Analysis of N-acylethanolamines in plasma and in the brain was performed using the liquid chromatography-mass spectrometry technique. In vitro and in vivo experiments show that synaptamide (1) reduces cold allodynia, (2) improves working memory and locomotor activity, (3) stabilizes neurogenesis and astroglial activity, (4) enhances the expression of NGF and NMDAR1, (5) increases the concentration of Ca2+ in astrocytes, and (6) increases the production of N-acylethanolamines. The results of the present study demonstrate that synaptamide affects the activity of hippocampal astroglia, resulting in faster recovery after CCI.

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

“…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 ]. 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 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 ]. as well as stabilizes astroglial activity and increases the expression of nerve growth factor (NGF) and two subunits of N-methyl-D-aspartate (NMDA) receptors in the hippocampus 14 days after nerve trauma [ 25 ].…”

“…Synaptamide also improves neurogenesis in the dentate gyrus subgranular zone of the hippocampus 14- and 35-days post-injury [ 24 , 25 ]. as well as stabilizes astroglial activity and increases the expression of nerve growth factor (NGF) and two subunits of N-methyl-D-aspartate (NMDA) receptors in the hippocampus 14 days after nerve trauma [ 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 ].…”

“…as well as stabilizes astroglial activity and increases the expression of nerve growth factor (NGF) and two subunits of N-methyl-D-aspartate (NMDA) receptors in the hippocampus 14 days after nerve trauma [ 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 ].…”

Mechanisms of Neuropathic Pain and Pain-Relieving Effects of Exercise Therapy in a Rat Neuropathic Pain Model

“… 32 Cognitive and emotional-behavioral impairments caused by the onset of neuropathic pain are associated with hippocampal neurogenic deficits. 34 Neuropathic pain has also been reported to inhibit differentiation into mature neurons in the hippocampal dentate gyrus region in parallel with reduced survival of neoplastic cells. 17 It has been reported that exercise works to prevent the onset of pain and eliminate pain after injury, and 58/64 (90%) articles published on the topic of exercise-induced analgesia showed a positive effect of exercise with only one activity.…”