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Chronic social isolation generates a persistent state of stress associated with obesity along with some neuro-endocrine disorders and central behavioral sequelae (eg anxiety, depression, aggression, and allodynia). In this study, we evaluated the effect of social isolation on body weight, depressive- and anxious-aggressive-like behavior, as well as on phenotypic changes of adipocytes from visceral adipose tissue of control (group-housed) or socially isolated (single-housed) male mice. The effect of treatment with pentadecyl-2-oxazoline (PEA-OXA), a natural alpha2 antagonist and histamine H3 protean partial agonist, on these alterations was also evaluated. Single or group-housed mice treated with vehicle or PEA-OXA underwent body weight, mechanical allodynia, anxious-, depressive- and aggressive-like behavior measurements. Proliferation rate, apoptosis, senescence, expression of fat lineage genes, lipid droplets and proinflammatory cytokines were measured on white adipose tissue adipocytes from group- or single-housed mice. Single housed mice developed weight gain, mechanical allodynia at the von Frey test, aggressiveness in the resident intruder test, depression- and anxiety-like behavior in the tail suspension and hole drop tests, respectively. Single housed mice receiving PEA-OXA showed a general resolution of both, physical-metabolic and behavioral alterations associated with social isolation. Furthermore, adipocytes from the adipose tissue of socially isolated mice showed an evident inflamed phenotype (i.e. a reduced rate of proliferation, apoptosis, senescence, and ROS hyper-production together with an increased expression of IL-1β, IL-10, IL-17, and TNF-α and a decrease of IL-6). The treatment with PEA-OXA on adipocytes from single housed mice produced a protective/anti-inflammatory phenotype with an increased expression of brown adipose tissue biomarker. This study confirms that persistent stress caused by social isolation predisposes to obesity and neuropsychiatric disorders. PEA-OXA, through its multi-target activity on alpha2 adrenoceptor and histamine H3 receptors, which have recently aroused great interest in the neuropsychiatric field, reduces weight gain, systemic pro-inflammatory state, allodynia, and affective disorders associated with social isolation.

Central post-stroke pain (CPSP) and associated depression remain poorly understood and pharmacological treatments are unsatisfactory. Recently, microglia activation was suggested to be involved in CPSP pathophysiology. The goal of this study was to investigate the effectiveness of a co-ultramicronized combination of N-palmitoylethanolamide and luteolin (PEALut) in a mouse model of thalamic hemorrhage (TH)-induced CPSP. TH was established through the collagenase-IV injection in thalamic ventral-posterolateral-nucleus. PEALut effects in CPSP-associated behaviors were evaluated during a 28-days observation period. We found that repeated administrations of co-ultra PEALut significantly reduced mechanical hypersensitivity after TH, as compared to vehicle, by reducing the early microglial activation in the perilesional site. Moreover, PEALut prevented the development of depressive-like behavior (21 days post-TH). These effects were associated with the restoration of synaptic plasticity in LEC-DG pathway and monoamines levels found impaired in TH mice. Hippocampal MED1 and TrkB expressions were significantly increased in TH compared to sham mice 21 days post-TH, whereas BDNF levels were decreased. PEALut restored MED1/TrkB/BDNF expression in mice. Remarkably, we found significant overexpression of MED1 in the human autoptic brain specimens after stroke, indicating a translational potential of our findings. These results pave the way for better-investigating depression in TH- induced CPSP, together with the involvement of MED1/TrkB/BDNF pathway, proposing PEALut as an adjuvant treatment.

Neuropathic pain has long-term consequences in terms of affective and cognitive disturbances suggesting the involvement of supraspinal mechanisms. In the present study, we used the spared nerve injury (SNI) model to characterize the development of sensory and aversive components of neuropathic pain, and to determine their electrophysiological impact across PFC and limbic regions. Moreover, we evaluated the regulation of several genes involved in immune response and inflammation triggered by the SNI.We showed that SNI led to sensorial hypersensitivity (cold and mechanical stimuli) and depressive-like behavior lasting 12 months after nerve injury. Interestingly, changes in non-emotional cognitive tasks (novel object recognition and Y maze) showed in 1-month SNI mice, were not evident normal in 12 months-SNI animals. In vivo electrophysiology revealed an impaired the Long Term Potentiation (LTP) at prefrontal cortex (PFC)- nucleus accumbens core (NAcore) pathway in both 1 and 12 months SNI. On the other hand, a reduced neural activity was recorded in the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway in 1 month-, but not in 12 months- SNI mice. Finally, we observed the upregulation of specific genes involved in involved in immune response in the hippocampus of 1 month-, but not 12 months-SNI mice, suggesting a neuroinflammatory response which may contribute to the SNI phenotype.These data suggest that distinct brain circuits may drive the psychiatric components of neuropathic pain and pave the way for better investigate the long-term consequences of peripheral nerve injury in which most of the available drugs are to date unsatisfactory.

The 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)-butyric acid, homo-AMPA, an analog of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and 2-aminoadipic acid, has shown no activity towards ionotropic and metabotropic glutamate 1, 2, 3, 4, 5, and 7 receptors (mGluR1-7), agonist activity at mGluR6 while the activity at mGluR8 was never investigated. The effect of homo-AMPA on pain control has been never investigated. In this study we evaluated the effect of intra-ventrolateral periaqueductal grey (VL PAG) microinjections of homo-AMPA on pain responses and the activity of pain-responding neurons of the rostral ventromedial medulla (RVM), the "pronociceptive" ON cells, and the "antinociceptive" OFF cells. The study was performed in control and diabetic neuropathic mice. Homo-AMPA decreased mechanical allodynia in diabetic neuropathic mice. Homo-AMPA increased also the latency to tail-flick, decreased the ongoing activity, the pain stimulus-evoked burst of firing, and the duration of the burst of the ON cells in both, control and neuropathic mice. Homo-AMPA also increased the ongoing activity, decreased and delayed the pause of the OFF cells in control mice. Unlike the retina, we did not find the transcript and protein for mGluR6 in the VL PAG. Alpha-methyl-serine-O-phosphate, a group III mGluRs antagonist, blocked the anti-allodynic effect of homo-AMPA. Considering the absence of both, mGluR6 in VL-PAG and homo-AMPA activity at mGluR4 and mGluR7 at the dose used, mGluR8 could be the target on which homo-AMPA produces the observed effects. The target of homo-AMPA capable of evoking analgesia at a very low dose and in conditions of diabetic neuropathy deserves further consideration.

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells, (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines, (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas, (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI), (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.