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Cancer-related cognitive impairment (CRCI) is a major neurotoxicity affecting more than 50% of cancer survivors. The underpinning mechanisms are mostly unknown, and there are no FDA-approved interventions. Sphingolipidomic analysis of mouse prefrontal cortex and hippocampus, key sites of cognitive function, revealed that cisplatin increased levels of the potent signaling molecule sphingosine-1-phosphate (S1P) and led to cognitive impairment. At the biochemical level, S1P induced mitochondrial dysfunction, activation of NOD-, LRR-, and pyrin domain-containing protein 3 inflammasomes, and increased IL-1[beta] formation. These events were attenuated by systemic administration of the functional S1P receptor 1 (S1PR1) antagonist FTY720, which also attenuated cognitive impairment without adversely affecting locomotor activity. Similar attenuation was observed with ozanimod, another FDA-approved functional S1PR1 antagonist. Mice with astrocyte-specific deletion of S1pr1 lost their ability to respond to FTY720, implicating involvement of astrocytic S1PR1. Remarkably, our pharmacological and genetic approaches, coupled with computational modeling studies, revealed that cisplatin increased S1P production by activating TLR4. Collectively, our results identify the molecular mechanisms engaged by the S1P/S1PR1 axis in CRCI and establish S1PR1 antagonism as an approach to target CRCI with therapeutics that have fast-track clinical application.

Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of S1pr1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.

Cisplatin is used to combat solid tumors. However, patients treated with cisplatin often develop cognitive impairments, sensorimotor deficits, and peripheral neuropathy. There is no FDA-approved treatment for these neurotoxicities. We investigated the capacity of a highly selective A 3 adenosine receptor (AR) subtype (A 3 AR) agonist, MRS5980, to prevent and reverse cisplatin-induced neurotoxicities. MRS5980 prevented cisplatin-induced cognitive impairment (decreased executive function and impaired spatial and working memory), sensorimotor deficits, and neuropathic pain (mechanical allodynia and spontaneous pain) in both sexes. At the structural level, MRS5980 prevented the cisplatin-induced reduction in markers of synaptic integrity. In-situ hybridization detected Adora3 mRNA in neurons, microglia, astrocytes and oligodendrocytes. RNAseq analysis identified 164 genes, including genes related to mitochondrial function, of which expression was changed by cisplatin and normalized by MRS5980. Consistently, MRS5980 prevented cisplatin-induced mitochondrial dysfunction and decreased signs of oxidative stress. Transcriptomic analysis showed that the A 3 AR agonist upregulates genes related to repair pathways including NOTCH1 signaling and chromatin modification in the cortex of cisplatin-treated mice. Importantly, A 3 AR agonist administration after completion of cisplatin treatment resolved cognitive impairment, neuropathy and sensorimotor deficits. Our results highlight the efficacy of a selective A 3 AR agonist to prevent and reverse cisplatin-induced neurotoxicities via preventing brain mitochondrial damage and activating repair pathways. An A 3 AR agonist is already in cancer, clinical trials and our results demonstrate management of neurotoxic side effects of chemotherapy as an additional therapeutic benefit.

Acute inflammation is particularly relevant in the pathogenesis of visceral hypersensitivity associated with inflammatory bowel diseases. Glia within the enteric nervous system, as well as within the central nervous system, contributes to neuroplasticity during inflammation, but whether enteric glia has the potential to modify visceral sensitivity following colitis is still unknown. This work aimed to investigate the occurrence of changes in the neuron–glial networks controlling visceral perception along the gut–brain axis during colitis, and to assess the effects of peripheral glial manipulation. Enteric glia activity was altered by the poison fluorocitrate (FC; 10 µmol kg−1 i.p.) before inducing colitis in animals (2,4-dinitrobenzenesulfonic acid, DNBS; 30 mg in 0.25 mL EtOH 50%), and visceral sensitivity, colon damage, and glia activation along the pain pathway were studied. FC injection significantly reduced the visceral hyperalgesia, the histological damage, and the immune activation caused by DNBS. Intestinal inflammation is associated with a parallel overexpression of TRPV1 and S100β along the gut–brain axis (colonic myenteric plexuses, dorsal root ganglion, and periaqueductal grey area). This effect was prevented by FC. Peripheral glia activity modulation emerges as a promising strategy for counteracting visceral pain induced by colitis.

The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell A3ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing, but unknown. The present study discovered that Rag-KO mice lacking T and B cells, as compared with WT mice, are insensitive to the anti-allodynic effects of A3AR agonists. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of CD4+ T cells from WT mice infiltrated the dorsal root ganglion (DRG) and restored A3AR agonist-mediated anti-allodynia in Rag-KO mice. CD4+ T cells from Adora3-KO or Il10-KO mice did not. Transfer of CD4+ T cells from WT mice, but not Il10-KO mice, into Il10-KO mice or Adora3-KO mice fully reinstated the anti-allodynic effects of A3AR activation. Notably, A3AR agonism reduced DRG neuron excitability when cocultured with CD4+ T cells in an IL-10-dependent manner. A3AR action on CD4+ T cells infiltrated in the DRG decreased phosphorylation of GluN2B-containing N-methyl-D-aspartate receptors at Tyr1472, a modification associated with regulating neuronal hypersensitivity. Our findings establish that activation of A3AR on CD4+ T cells to release IL-10 is required and sufficient evidence for the use of A3AR agonists as therapeutics.

The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell A3ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing, but unknown. The present study discovered that Rag-KO mice lacking T and B cells, as compared with WT mice, are insensitive to the anti-allodynic effects of A3AR agonists. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of CD4+ T cells from WT mice infiltrated the dorsal root ganglion (DRG) and restored A3AR agonist-mediated anti-allodynia in Rag-KO mice. CD4+ T cells from Adora3-KO or II10-KO mice did not. Transfer of CD4+ T cells from WT mice, but not II10-KO mice, into II10-KO mice or Adora3-KO mice fully reinstated the anti-allodynic effects of A3AR activation. Notably, A3AR agonism reduced DRG neuron excitability when cocultured with CD4+ T cells in an IL-10-dependent manner. A3AR action on CD4+ T cells infiltrated in the DRG decreased phosphorylation of GluN2B-containing N-methyl-D-aspartate receptors at Tyr1472, a modification associated with regulating neuronal hypersensitivity. Our findings establish that activation of A3AR on CD4+ T cells to release IL-10 is required and sufficient evidence for the use of A3AR agonists as therapeutics.

The [A.sub.3] adenosine receptor ([A.sub.3]AR) has emerged as a therapeutic target with [A.sub.3]AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell [A.sub.3]ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of [A.sub.3]AR agonists is enticing, but unknown. The present study discovered that Rag- KO mice lacking T and B cells, as compared with WT mice, are insensitive to the anti-allodynic effects of [A.sub.3]AR agonists. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of [CD4.sup.+] T cells from WT mice infiltrated the dorsal root ganglion (DRG) and restored [A.sub.3]AR agonist-mediated anti-allodynia in Rag-KO mice. [CD4.sup.+] T cells from Adora3-KO or Il10-KO mice did not. Transfer of [CD4.sup.+] T cells from WT mice, but not Il10-KO mice, into Il10- KO mice or Adora3-KO mice fully reinstated the anti-allodynic effects of [A.sub.3]AR activation. Notably, [A.sub.3]AR agonism reduced DRG neuron excitability when cocultured with [CD4.sup.+] T cells in an IL-10-dependent manner. [A.sub.3]AR action on [CD4.sup.+] T cells infiltrated in the DRG decreased phosphorylation of GluN2B-containing N-methyl-D-aspartate receptors at Tyr1472, a modification associated with regulating neuronal hypersensitivity. Our findings establish that activation of [A.sub.3]AR on [CD4.sup.+] T cells to release IL-10 is required and sufficient evidence for the use of [A.sub.3]AR agonists as therapeutics.

Cisplatin is used to combat solid tumors. However, patients treated with cisplatin often develop cognitive impairments, sensorimotor deficits, and peripheral neuropathy. There is no FDA-approved treatment for these neurotoxicities. We investigated the capacity of a highly selective A adenosine receptor (AR) subtype (A AR) agonist, MRS5980, to prevent and reverse cisplatin-induced neurotoxicities. MRS5980 prevented cisplatin-induced cognitive impairment (decreased executive function and impaired spatial and working memory), sensorimotor deficits, and neuropathic pain (mechanical allodynia and spontaneous pain) in both sexes. At the structural level, MRS5980 prevented the cisplatin-induced reduction in markers of synaptic integrity. In-situ hybridization detected Adora3 mRNA in neurons, microglia, astrocytes and oligodendrocytes. RNAseq analysis identified 164 genes, including genes related to mitochondrial function, of which expression was changed by cisplatin and normalized by MRS5980. Consistently, MRS5980 prevented cisplatin-induced mitochondrial dysfunction and decreased signs of oxidative stress. Transcriptomic analysis showed that the A AR agonist upregulates genes related to repair pathways including NOTCH1 signaling and chromatin modification in the cortex of cisplatin-treated mice. Importantly, A AR agonist administration after completion of cisplatin treatment resolved cognitive impairment, neuropathy and sensorimotor deficits. Our results highlight the efficacy of a selective A AR agonist to prevent and reverse cisplatin-induced neurotoxicities via preventing brain mitochondrial damage and activating repair pathways. An A AR agonist is already in cancer, clinical trials and our results demonstrate management of neurotoxic side effects of chemotherapy as an additional therapeutic benefit.

Chemotherapy-induced peripheral neuropathy accompanied by neuropathic pain (CIPN) is a major neurotoxicity of cisplatin, a platinum-based drug widely used for lung, ovarian, and testicular cancer treatment. CIPN causes drug discontinuation and severely impacts life quality with no FDA-approved interventions. We previously reported that platinum-based drugs increase levels of sphingosine 1-phosphate (S1P) in the spinal cord and drive CIPN through activating the S1P receptor subtype 1 (S1PR1). However, the mechanisms engaged downstream of S1PR1 remain poorly understood. Using single cell transcriptomics on male mouse spinal cord, our findings uncovered subpopulation-specific responses to cisplatin associated with CIPN. Particularly, cisplatin increased the proportion of astrocytes with high expression levels of ( astrocytes), specific to which a Wnt signaling pathway was identified. To this end, several genes involved in Wnt signaling, such as the fibroblast growth factor receptor 3 gene ( ), were highly expressed in astrocytes. The functional S1PR1 antagonist, ozanimod, prevented cisplatin-induced neuropathic pain and astrocytic upregulation of the Wnt signaling pathway genes. FGFR3 belongs to the FGF/FGFR family which often signals to activate Wnt signaling. Intrathecal injection of the FGFR3 antagonist, PD173074, prevented the development of CIPN in male mice. These data not only highlight FGFR3 as one of the astrocytic targets of S1PR1 but raise the possibility that S1PR1-induced engagement of Wnt signaling in astrocytes may contribute to CIPN. Overall, our results provide a comprehensive mapping of cellular and molecular changes engaged in cisplatin-induced neuropathic pain and decipher novel S1PR1-based mechanisms of action.

Niaprazine is a sedative-hypnotic drug initially developed as an antihistamine and used for its notable sedative effects, particularly in children. Following its withdrawal from the market by the producer, the drug has been administered as magistral formulations available in syrup form, but there are several important disadvantages to this, including instability, taste issues, lack of controlled release, and the potential for unreliable dosing due to incomplete swallowing. There is also an increased risk of dental caries, as well as the fact that these formulations are not suitable for children who suffer from diabetes. The purpose of the current investigation is to prepare and characterize xanthan gum-based gels for the oral administration of niaprazine. Niaprazine gels appear as transparent-whiteish, non-sticky substances, with the drug uniformly dispersed throughout the systems. They are also stable over time. Dynamic rheology revealed their advantageous shear-thinning properties, which enable the formulation to be flexibly dosed orally through administration via syringe. During experimentation, the evaluation of the mucoadhesion features and the in vitro drug release profile were also performed. The results demonstrate that the formulation may represent an alternative to niaprazine syrup, allowing easy preparation, administration, and increased compliance in various categories of patients, including pediatric.