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

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

Synaptamide Ameliorates Hippocampal Neurodegeneration and Glial Activation in Mice with Traumatic Brain Injury

Traumatic brain injury (TBI) is a major concern for public health worldwide, affecting 55 million people and being the leading cause of death and disability. To improve the outcomes and effectiveness of treatment for these patients, we conducted a study on the potential therapeutic use of N-docosahexaenoylethanolamine (synaptamide) in mice using the weight-drop injury (WDI) TBI model. Our study focused on exploring synaptamide’s effects on neurodegeneration processes and changes in neuronal and glial plasticity. Our findings showed that synaptamide could prevent TBI-associated working memory decline and neurodegenerative changes in the hippocampus, and it could alleviate decreased adult hippocampal neurogenesis. Furthermore, synaptamide regulated the production of astro- and microglial markers during TBI, promoting the anti-inflammatory transformation of the microglial phenotype. Additional effects of synaptamide in TBI include stimulating antioxidant and antiapoptotic defense, leading to the downregulation of the Bad pro-apoptotic marker. Our data suggest that synaptamide has promising potential as a therapeutic agent to prevent the long-term neurodegenerative consequences of TBI and improve the quality of life

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

Synaptamide Improves Cognitive Functions and Neuronal Plasticity in Neuropathic Pain

Neuropathic pain arises from damage or dysfunction of the peripheral or central nervous system and manifests itself in a wide variety of sensory symptoms and cognitive disorders. Many studies demonstrate the role of neuropathic pain-induced neuroinflammation in behavioral disorders. For effective neuropathic pain treatment, an integrative approach is required, which simultaneously affects several links of pathogenesis. One promising candidate for this role is synaptamide (N-docosahexaenoylethanolamine), which is an endogenous metabolite of docosahexaenoic acid. In this study, we investigated the activity of synaptamide on mice behavior and hippocampal plasticity in neuropathic pain induced by spared nerve injury (SNI). We found a beneficial effect of synaptamide on the thermal allodynia and mechanical hyperalgesia dynamics. Synaptamide prevented working and long-term memory impairment. These results are probably based on the supportive effect of synaptamide on SNI-impaired hippocampal plasticity. Nerve ligation caused microglia activation predominantly in the contralateral hippocampus, while synaptamide inhibited this effect. The treatment reversed dendritic tree degeneration, dendritic spines density reduction on CA1-pyramidal neurons, neurogenesis deterioration, and hippocampal long-term potentiation (LTP) impairment. In addition, synaptamide inhibits changes in the glutamatergic receptor expression. Thus, synaptamide has a beneficial effect on hippocampal functioning, including synaptic plasticity and hippocampus-dependent cognitive processes in neuropathic pain

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

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

Fatty Acid-Derived <i>N</i>-acylethanolamines Dietary Supplementation Attenuates Neuroinflammation and Cognitive Impairment in LPS Murine Model

Neuroinflammation plays a critical role in the pathogenesis of most neurological and neurodegenerative diseases and therefore represents a potential therapeutic target. In this regard, accelerating the resolution process in chronic neuroinflammation may be an effective strategy to deal with the cognitive consequences of neuropathology and generalized inflammatory processes. N-acylethanolamine (NAE) derivatives of fatty acids, being highly active lipid mediators, possess pro-resolving activity in inflammatory processes and are promising agents for the suppression of neuroinflammation and its consequences. This paper is devoted to a study of the effects played by dietary supplement (DS), containing a composition of fatty acid-derived NAEs, obtained from squid Berryteuthis magister, on the hippocampal neuroinflammatory and memory processes. By detecting the production of pro-inflammatory cytokines and glial markers, a pronounced anti-inflammatory activity of DS was demonstrated both in vitro and in vivo. DS administration reversed the LPS-induced reduction in hippocampal neurogenesis and memory deterioration. LC-MS analysis revealed an increase in the production of a range of NAEs with well-documented anti-inflammatory activity in response to the administered lipid composition. To conclude, we found that tested DS suppresses the neuroinflammatory response by reducing glial activation, positively regulates neural progenitor proliferation, and attenuates hippocampal-dependent memory impairment

N-Docosahexanoylethanolamine Reduces Microglial Activation and Improves Hippocampal Plasticity in a Murine Model of Neuroinflammation

Chronic neuroinflammation is a common pathogenetic link in the development of various neurological and neurodegenerative diseases. Thus, a detailed study of neuroinflammation and the development of drugs that reduce or eliminate the negative effect of neuroinflammation on cognitive processes are among the top priorities of modern neurobiology. N-docosahexanoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analog of anandamide, an essential endocannabinoid produced from arachidonic acid. Our study aims to elucidate the pharmacological activity of synaptamide in lipopolysaccharide (LPS)-induced neuroinflammation. Memory deficits in animals were determined using behavioral tests. To study the effects of LPS (750 &micro;g/kg/day, 7 days) and synaptamide (10 mg/kg/day, 7 days) on synaptic plasticity, long-term potentiation was examined in the CA1 area of acute hippocampal slices. The Golgi&ndash;Cox method allowed us to assess neuronal morphology. The production of inflammatory factors and receptors was assessed using ELISA and immunohistochemistry. During the study, functional, structural, and plastic changes within the hippocampus were identified. We found a beneficial effect of synaptamide on hippocampal synaptic plasticity and morphological characteristics of neurons. Synaptamide treatment recovered hippocampal neurogenesis, suppressed microglial activation, and significantly improved hippocampus-dependent memory. The basis of the phenomena described above is probably the powerful anti-inflammatory activity of synaptamide, as shown in our study and several previous works

Anti-Inflammatory Activity of N-Docosahexaenoylethanolamine and N-Eicosapentaenoylethanolamine in a Mouse Model of Lipopolysaccharide-Induced Neuroinflammation

The search for methods of cognitive impairment treatment and prevention in neurological and neurodegenerative diseases is an urgent task of modern neurobiology. It is now known that various diseases, accompanied by dementia, exhibit a pronounced neuroinflammation. Considering the significant docosahexaenoic and eicosapentaenoic polyunsaturated fatty acids’ therapeutic potential, we decided to investigate and compare anti-inflammatory activity of their N-acylethanolamine derivatives. As a result, we found that both N-docosahexaenoylethanolamine (synaptamide) and N-eicosapentaenoylethanolamine (EPEA) prevents an LPS-mediated increase in the proinflammatory cytokines TNF-α and IL-6 production in the SIM-A9 microglia culture. In an in vivo experiment, synaptamide reversed an increase in LPS-mediated hippocampal TNF-α and IL-1β, but EPEA did not. However, both compounds contributed to the microglia polarization towards the M2-phenotype. Synaptamide, rather than EPEA, inhibited the Iba-1-positive microglia staining area increase. However, both synaptamide and EPEA prevented the LPS-mediated astrogliosis. A study of BDNF immunoreactivity showed that synaptamide, but not EPEA, reversed an LPS-mediated decrease in BDNF production. Despite the more pronounced anti-inflammatory activity of synaptamide, both compounds were effective in maintaining a normal level of hippocampal long-term potentiation in neuroinflammation. The results indicate a high therapeutic potential for both compounds. However, some tests have shown higher activity of synaptamide compared to EPEA

Synaptamide Modulates Astroglial Activity in Mild Traumatic Brain Injury

At present, the study of the neurotropic activity of polyunsaturated fatty acid ethanolamides (N-acylethanolamines) is becoming increasingly important. N-docosahexaenoylethanolamine (synaptamide, DHEA) is a highly active metabolite of docosahexaenoic acid (DHA) with neuroprotective, synaptogenic, neuritogenic, and anti-inflammatory properties in the nervous system. Synaptamide tested in the present study was obtained using a chemical modification of DHA isolated from squid Berryteuthis magister liver. The results of this study demonstrate the effects of synaptamide on the astroglial response to injury in the acute (1 day) and chronic (7 days) phases of mild traumatic brain injury (mTBI) development. HPLC-MS study revealed several times increase of synaptamide concentration in the cerebral cortex and serum of experimental animals after subcutaneous administration (10 mg/kg/day). Using immunohistochemistry, it was shown that synaptamide regulates the activation of GFAP- and S100&beta;-positive astroglia, reduce nNOS-positive immunostaining, and stimulates the secretion of neurotrophin BDNF. Dynamics of superoxide dismutase production in synaptamide treatment confirm the antioxidant efficacy of the test compound. We found a decrease in TBI biomarkers such as GFAP, S100&beta;, and IL-6 in the blood serum of synaptamide-treated experimental animals using Western blot analysis. The results indicate the high therapeutic potential of synaptamide in reducing the severity of the brain damage consequences