Chronic neuropathic pain is a condition that causes both sensory disturbances and a variety of functional disorders, indicating the involvement of various brain structures in pain pathogenesis. One of the factors underlying chronic neuropathic pain is neuroinflammation, which is accompanied by microglial activation and pro-inflammatory factor release. N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endocannabinoid-like metabolite synthesized endogenously from docosahexaenoic acid. Synaptamide exhibits anti-inflammatory activity and improves neurite outgrowth, neurogenesis, and synaptogenesis within the hippocampus. This study aims to evaluate the effects of synaptamide obtained by the chemical modification of DHA, extracted from the Far Eastern raw material Berryteuthis magister on neuroinflammatory response and hippocampal neurogenesis changes during neuropathic pain. The study of microglial protein and cytokine concentrations was performed using immunohistochemistry and ELISA. The brain lipid analysis was performed using the liquid chromatography-mass spectrometry technique. Behavioral experiments showed that synaptamide prevented neuropathic pain-associated sensory and behavioral changes, such as thermal allodynia, impaired locomotor activity, working and long-term memory, and increased anxiety. Synaptamide attenuated microglial activation, release of proinflammatory cytokines, and decrease in hippocampal neurogenesis. Lipid analysis revealed changes in the brain N-acylethanolamines composition and plasmalogen concentration after synaptamide administration. In conclusion, we show here that synaptamide may have potential for use in preventing or treating neuropathic cognitive pain and emotional effects.

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.

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/mm³ in CCI+Syn, compared to 80,288 ± 4,287 cells/mm³ 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.

N-docosahexaenoylethanolamine (DHEA), or synaptamide, is an endogenous metabolite of docosahexaenoic acid (DHA) that exhibits synaptogenic and neurogenic effects. In our previous studies, synaptamide administration inhibited the neuropathic pain-like behavior and reduced inflammation in the central nervous system following sciatic nerve injury. In the present study, we examine the effect of synaptamide on the peripheral nervous system in a neuropathic pain condition. The dynamics of ionized calcium-binding adapter molecule 1 (iba-1), CD68, CD163, myelin basic protein, and the production of interleukin 1β and 6 within the sciatic nerve, as well as the neuro-glial index and the activity of iba-1, CD163, glial fibrillary acidic protein (GFAP), neuronal NO synthase (nNOS), substance P (SP), activating transcription factor 3 (ATF3) in the dorsal root ganglia (DRG), are studied. According to our results, synaptamide treatment (4 mg/kg/day) (1) decreases the weight-bearing deficit after nerve trauma; (2) enhances the remyelination process in the sciatic nerve; (3) shows anti-inflammatory properties in the peripheral nervous system; (4) decreases the neuro-glial index and GFAP immunoreactivity in the DRG; (5) inhibits nNOS- and SP-ergic activity in the DRG, which might contribute to neuropathic pain attenuation. In general, the current study demonstrates the complex effect of synaptamide on nerve injury, which indicates its high potential for neuropathic pain management.

The dentate gyrus of the hippocampus is the primary location of adult neurogenesis, which is affected by a variety of external and internal factors, including activity of surrounding glial cells. This study concerns alterations in hippocampal neurogenesis and changes in activity of both proinflammatory and neuroprotective microglia/macrophages after sciatic nerve injury in the rat. Here, we demonstrated that the chronic pain induced by a peripheral nerve injury manifests in the hippocampus by a decrease in proliferation (PCNA+) and neurogenesis (DCX+), an increase in proinflammatory cytokines (CD86+), and a reduction in neuroprotective (CD163+) microglia/macrophages. We suggest that a pathological increase microglia/macrophage activity is the cause of neurogenesis suppression observed in chronic neuropathic pain.