We moved from the hypothesis that perineuronal nets (PNNs), which are condensed structures of the extracellular matrix surrounding GABAergic interneurons in the forebrain, contribute to mechanisms of maladaptive neuronal plasticity underlying chronic pain. Here, we found that the density of PNNs labelled with the lectin Wisteria Floribunda Agglutinin (WFA) increased in the contralateral somatosensory cortex (SSC), medial prefrontal cortex (mPFC), reticular thalamic nucleus (RTN), and insular cortex of mice developing neuropathic pain in response to unilateral chronic constriction injury of the sciatic nerve. These regions are involved in neuronal circuits underlying perception, sufferance, embodiment, and top-down control of pain. At least in the SSC and mPFC, the increased density of WFA⁺ PNNs was associated with an up-regulation of the proteoglycans, brevican and neurocan, as shown by immunoblot analysis. Enzymatic degradation of PNNs caused by local infusion of chondroitinase ABC in the contralateral SSC or RTN enhanced both mechanical and thermal pain thresholds in chronic constriction injury mice. In contrast, siRNA-induced knock-down of the PNN-degrading enzyme, type-9 matrix metalloproteinase (MMP-9), in the SSC or RTN lowered pain thresholds in sham-operated mice. These data, combined with our previous findings obtained in mice with chronic inflammatory pain, suggest that an enhanced formation/reduced degradation of WFA⁺ PNNs in regions of the pain matrix is associated with different types of chronic pain and may drive mechanisms of nociceptive sensitization leading to reduced mechanical and thermal pain thresholds.

Background: Schizophrenia with comorbid substance use disorder (SUD) is associated with greater clinical severity, poorer adherence, and worse functional outcomes. Third-generation antipsychotics, through partial dopamine agonism, may represent a useful strategy in this complex population. This study compared the long-term efficacy of brexpiprazole and aripiprazole in patients with schizophrenia, with or without comorbid SUD. Methods: Patients (N = 243) with DSM-5/DSM-5-TR schizophrenia orally received 4 mg/day brexpiprazole or 30 mg/day aripiprazole for 12 months in a real-world clinical setting. Psychopathology was assessed at baseline and after 1, 3, 6, and 12 months using the Brief Psychiatric Rating Scale (BPRS) and the Positive And Negative Syndrome Scale (PANSS). Analyses were performed on 217 completers, excluding 26 drop-outs. Outcomes were compared according to drug and presence/absence of comorbid SUD. Results: Both brexpiprazole and aripiprazole were associated with psychotic symptom and global psychopathology improvement over 12 months (p < 0.01). In patients without SUD, the two treatments showed comparable efficacy. Among patients with comorbid SUD, brexpiprazole showed greater improvement in BPRS and PANSS outcomes than aripiprazole (p < 0.01). Treatment response to aripiprazole, but not to brexpiprazole, was diminished by substance use. Brexpiprazole was associated with better tolerability and lower rates of subjective agitation-related discontinuation. Conclusions: Both dopamine partial agonists were effective in treating schizophrenia; however, brexpiprazole was superior in patients with comorbid SUD. Findings suggest that brexpiprazole may represent a promising therapeutic option in dual-disorder patients.

Background: Multiple sclerosis (MS) is an immune-mediated and demyelinating disease affecting oligodendrocytes, leading to neurodegeneration. Immunocompromised individuals may have a reduced antibody response after vaccination, and this insufficient immune response in COVID-19 individuals might contribute to the pathophysiology of MS. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the angiotensin-converting enzyme 2 (ACE2) to entry into the host’s cell and infect human cells. Objective: Evaluation of the effects of drugs for the treatment of MS, such as fingolimod, cladribine, dimethyl fumarate, and teriflunomide, on the expression of ACE2 in human lung carcinoma cell lines. Methods: We used Calu-3 human lung adenocarcinoma cells, physiologically expressing the ACE2 gene, and A549-hACE2-TMPRSS2 human lung carcinoma cells, overexpressing the human ACE2 gene, and challenged them with the pro-inflammatory interleukin-1β (IL-1β) in the presence or absence of MS drugs, and assessed ACE2 mRNA and protein levels. Results: MS drugs affected ACE2 mRNA and protein levels differently in Calu-3 and A549-hACE2-TMPRSS2 cells. Fingolimod (50 nM) significantly reduced ACE2 protein levels under inflammatory conditions in Calu-3 cells. Cladribine reduced ACE2 protein levels in A549-hACE2-TMPRSS2 cells. Dimethyl fumarate increased ACE2 protein levels in Calu-3 cells under both basal and pro-inflammatory conditions. Teriflunomide increased ACE2 protein levels in Calu-3 cells and ACE2 mRNA levels in A549-hACE2-TMPRSS2 cells, both in basal and pro-inflammatory conditions. Discussion: We incubated cells with drug concentrations similar to those found in the plasma of relapsing-remitting MS patients treated with disease-modifying drugs (DMD), although they act via different mechanisms. Fingolimod acts on sphingosine-1-phosphate receptors and inhibiting class 1 histone deacetylase could suppress ACE2 expression, independently of its immunosuppressive action, or might act at post-transcriptional levels. Fingolimod also stimulates the secretion of neurotrophic factors in the CNS and exerts neuroprotective effects. Conclusion: Data suggest that drugs used in the treatment of MS can modify ACE2 expression; specifically, fingolimod reduces ACE2 expression and may have a protective role against SARS-CoV-2 infection.

MGlu5 metabotropic glutamate receptors are highly expressed and functional in early postnatal life, but their role in brain development remains to be elucidated. We now report that mGlu5^−/− mice showed a large reduction in mRNA and protein levels of myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), and myelin basic protein (MBP) in the cerebral cortex and cerebellum at postnatal day (PND) 14. Expression of these proteins reflects oligodendrocyte differentiation and myelin formation in the CNS, a process that is prominent in the second week of postnatal life in mice. Expression of myelin markers recovered at later developmental stages, with the exception of MAG and MBP levels in the cerebellum, which were still reduced in mGlu5^−/− mice. We also observed a large reduction in myelin protein markers in the cerebral cortex and cerebellum of mice treated with the mGlu5 receptor negative allosteric modulator MTEP (3 mg/kg, i.p.) from PND 7 to PND 14. MTEP-treated mice also showed reduced motor coordination and sensorimotor function at PND 14. Treatment with MTEP reduced oligodendrocyte maturation without affecting proliferation of oligodendrocyte progenitor cells in primary cultures prepared from the rat cerebral cortex. These findings suggest that endogenous activation of mGlu5 receptors contributes to myelin formation during postnatal development in mice.