International journal of molecular sciences
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This study investigated whether metabotropic glutamate receptor (mGluR) 5 and 8 are involved in the effect of ultramicronizedpalmitoylethanolamide (um-PEA) on the cognitive behavior and long term potentiation (LTP) at entorhinal cortex (LEC)-dentate gyrus (DG) pathway in mice rendered neuropathic by the spare nerve injury (SNI). SNI reduced discriminative memory and LTP. Um-PEA treatment started after the development of neuropathic pain had no effects in sham mice, whereas it restored cognitive behavior and LTP in SNI mice. 2-Methyl-6-(phenylethynyl) pyridine (MPEP), a selective mGluR5 antagonist, improved cognition in SNI mice and produced a chemical long term depression of the field excitatory postsynaptic potentials (fEPSPs) in sham and SNI mice. ⋯ The effect of PEA on LTP and cognitive behavior was modulated by mGluR5 and mGluR8. In particular in the SNI conditions, the mGluR5 blockade facilitated memory and LTP, but prevented the beneficial effects of PEA on discriminative memory while the mGluR8 blockade, which was ineffective in itself, prevented the favorable action of the PEA on LTP. Thus, although their opposite roles (excitatory/inhibitory of the two receptor subtypes on the glutamatergic system), they appeared to be required for the neuroprotective effect of PEA in conditions of neuropathic pain.
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Theiler's murine encephalomyelitis (TME) represents a versatile animal model for studying the pathogenesis of demyelinating diseases such as multiple sclerosis. Hallmarks of TME are demyelination, astrogliosis, as well as inflammation. Previous studies showed that matrix metalloproteinase 12 knockout (Mmp12-/-) mice display an ameliorated clinical course associated with reduced demyelination. ⋯ However, a dominance of M1 cells was detected in the spinal cord of TMEV-infected mice at all time points. Reduced astrogliosis in Mmp12-/- mice was associated with a reduced density of activated/reactive microglia and a trend for a reduced density of M1 cells. This indicates that MMP12 plays an important role in microglia activation, polarization, and migration as well as astrogliosis and microglia/astrocyte interaction.
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Immunomodulatory and wound healing activities of adipose-derived stem cells (ADSCs) have been reported in various in vitro and in vivo experimental models suggesting their beneficial role in regenerative medicine and treatments of inflammatory-related disorders. Lipoma-derived stem cells (LDSCs) were reported as a potential tool in regenerative medicine due to the similarity with ADSCs but we have previously shown that LDSCs have different differentiation capacity than ADSCs despite a similar mesenchymal phenotype. To further analyze the potential differences and/or similarities between those two stem cell types, in the present study we examined the macrophages (MΦs)' response, immunomodulatory and wound healing effect of conditioned media (CM) of LDSCs and ADSCs in indirect co-culture system in vitro. ⋯ Anti-inflammatory potential of CM of LDSCs and ADSCs, with pronounced effect of LDSCs, in unstimulated RAW 264.7 MΦs was evaluated by decrease in Tnf and increase in Il10 gene expression, which was confirmed by corresponding cytokines' secretion analysis. Conditioned media of both LDSCs and ADSCs led to the functional activation of MΦs, with slightly more pronounced effect of CM of LDSCs, while both stimulated wound healing in vitro in a similar manner. Results of this study suggest that LDSCs secrete soluble factors like ADSCs and therefore may have a potential for application in regenerative medicine, due to immunomodulatory and wound healing activity, and indicate that LDSCs through secretome may interact with other cells in lipoma tissue.
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The analgesic effect of venlafaxine (VLX), which is a selective serotonin and noradrenaline reuptake inhibitor (SNRI), has been observed on oxaliplatin-induced neuropathic pain in mice. Significant allodynia was shown after oxaliplatin treatment (6 mg/kg, i.p.); acetone and von Frey hair tests were used to assess cold and mechanical allodynia, respectively. Intraperitoneal administration of VLX at 40 and 60 mg/kg, but not 10 mg/kg, significantly alleviated these allodynia. ⋯ In cold allodynia, the α₂-adrenergic antagonist idazoxan (10 μg, i.t.), but not the α₁-adrenergic antagonist prazosin (10 μg, i.t.), abolished VLX-induced analgesia. Furthermore, idazoxan and 5-HT₃ receptor antagonist bemesetron (MDL-72222, 15 μg, i.t.), but not prazosin or mixed 5-HT1, 2 receptor antagonist methysergide (10 μg, i.t.), abolished VLX-induced analgesia in mechanical allodynia. In conclusion, 40 mg/kg of VLX treatment has a potent relieving effect against oxaliplatin-induced neuropathic pain, and α₂-adrenergic receptor, and both α₂-adrenergic and 5-HT₃ receptors are involved in this effect of VLX on cold and mechanical allodynia, respectively.