7-Chloro-4-(Phenylselanyl) Quinoline Is a Novel Multitarget Therapy to Combat Peripheral Neuropathy and Comorbidities Induced by Paclitaxel in Mice

Paltian, Jaini J.; Reis, Angélica S.; Martins, Amanda W. S.; Blödorn, Eduardo B.; Dellagostin, Eduardo N.; Soares, Liane K.; Schumacher, Ricardo F.; Campos, Vinícius Farias; Alves, Diego; Luchese, Cristiane; Wilhelm, Ethel A.

doi:10.1007/s12035-022-02991-4

Cited by 6 publications

(4 citation statements)

References 91 publications

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“…This work confirmed the memory deficits caused by PTX, as previously demonstrated by the reduced discrimination index in the novel object recognition test [14], and further proved that the administration of HRW normalized this cognitive impairment. These results are in accordance with the prevention of stress-induced decline of memory produced by the continuous consumption of HRW in mice [53], with the efficacy of other gases in inhibiting the memory deficits associated with chronic osteoarthritis pain [54] as well as with those produced by 7-chloro-4-(phenylselanyl) quinoline in animals with PIPN [55]. Several works indicated the contribution of the plasticity changes in memory impairments and that several drugs can improve these deficits by restoring the altered expression of MAPK activated by chemotherapy in the CNS [14].…”

Section: Discussionsupporting

confidence: 81%

New Treatment for the Cognitive and Emotional Deficits Linked with Paclitaxel-Induced Peripheral Neuropathy in Mice

et al. 2022

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Chemotherapy-provoked peripheral neuropathy and its linked comorbidities severely reduce the quality of a patient’s life. Its therapy is not completely resolved and has become an important clinical challenge. The protective actions of molecular hydrogen (H2) in many neurological disorders have been described, but its effects on memory and the emotional deficits accompanying neuropathic pain induced by chemotherapy remain unknown. In this study, using male mice injected with paclitaxel (PTX), we examined the effects of systemic treatment with hydrogen-rich water (HRW) in: (i) the mechanical and thermal allodynia provoked by PTX and the pathways involved; (ii) the memory deficits, anxiety- and depressive-like behaviors associated with PTX-induced peripheral neuropathy (PIPN); and (iii) the plasticity (p-extracellular signal-regulated protein kinase; p-ERK ½), nociceptive (p-protein kinase B, p-Akt), inflammatory (p-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; p-IKBα), and oxidative (4-hydroxynonenal: 4-HNE) alterations provoked by PIPN in the prefrontal cortex (PFC). The results revealed: (1) the antiallodynic actions of HRW administered at one or two times per day during 7 and 3 consecutive days; (2) the participation of Kv7 potassium channels and the Nrf2-heme oxygenase 1-NAD(P)H: quinone oxidoreductase 1 pathway in the painkiller effects of HRW; (3) the inhibition of memory deficits and the anxiodepressive-like behaviors related with PIPN induced by HRW; and (4) the normalization of p-ERK ½, p-Akt and 4-HNE up-regulation and the activation of antioxidant enzymes produced by this treatment in PFC. This study proposes HRW as a possible effective and safe therapy for PIPN and its associated cognitive and emotional deficits.

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Section: Discussionsupporting

confidence: 81%

New Treatment for the Cognitive and Emotional Deficits Linked with Paclitaxel-Induced Peripheral Neuropathy in Mice

et al. 2022

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“…Unlike other chemotherapeutic agents that induce neuropathic pain, PTX exacerbates inflammatory conditions, contributing to the pathophysiology of peripheral neuropathy [ 9 ]. The involvement of the nitrergic pathway in PTX−induced neuropathic pain has been well documented, and modulation of this pathway holds promise for its treatment [ 21 , 22 ]. Interestingly, MTDZ administration reversed the elevated NOx levels in the cerebral cortex of male mice and in the spinal cord of female mice exposed to PTX.…”

Section: Discussionmentioning

confidence: 99%

The Antinociceptive Responses of MTDZ to Paclitaxel−Induced Peripheral Neuropathy and Acute Nociception in Mice: Behavioral, Pharmacological, and Biochemical Approaches

da Motta,

Martins,

Macedo

et al. 2023

Pharmaceuticals

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The efficacy of 5-((4-methoxyphenyl)thio)benzo[c][1,2,5] thiodiazole (MTDZ) in mitigating paclitaxel (PTX)-induced peripheral neuropathy was investigated in male and female Swiss mice. The study examined the effects of MTDZ on various pathways, including transient receptor potential cation channel subfamily V member 1 (TRPV1), glutamatergic, nitrergic, guanylate cyclase (cGMP), serotonergic, and opioidergic. Mice received intraperitoneal PTX (2 mg/kg) or vehicle on days 1, 2, and 3, followed by oral MTDZ (1 mg/kg) or vehicle from days 3 to 14. Mechanical and thermal sensitivities were assessed using Von Frey and hot plate tests on days 8, 11, and 14. The open field test evaluated locomotion and exploration on day 12. On day 15, nitrite and nitrate (NOx) levels and Ca2+−ATPase activity in the cerebral cortex and spinal cord were measured after euthanizing the animals. MTDZ administration reversed the heightened mechanical and thermal sensitivities induced by PTX in male and female mice without affecting locomotion or exploration. MTDZ also modulated multiple pathways, including glutamatergic, NO/L−arginine/cGMP, serotonergic (5−HT1A/1B), opioid, and TRPV1 pathways. Additionally, MTDZ reduced NOx levels and modulated Ca2+−ATPase activity. In conclusion, MTDZ effectively alleviated PTX−induced peripheral neuropathy and demonstrated multi-targeted modulation of pain-related pathways. Its ability to modulate multiple pathways, reduce NOx levels, and modulate Ca2+−ATPase activity makes it a potential pharmacological candidate for peripheral neuropathy, acute nociceptive, and inflammatory conditions. Further research is needed to explore its therapeutic potential in these areas.

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“…administered PTX diluted in saline (NaCl 0.9%) at a dose of 2 mg/kg every other day for a total of 4 injections (days 0, 2, 4, and 6). 34 , 35 , 36 The control group was i.p. administered the same volume of physiological saline.…”

Section: Methodsmentioning

confidence: 99%

“…To induce PIPN pain, male and female C57BL/6 mice were i.p. administered PTX diluted in saline (NaCl 0.9%) at a dose of 2 mg/kg every other day for a total of 4 injections (days 0, 2, 4, and 6) 34–36 . The control group was i.p.…”

Section: Methodsmentioning

confidence: 99%

Sex differences in PD‐L1‐induced analgesia in paclitaxel‐induced peripheral neuropathy mice depend on TRPV1‐based inhibition of CGRP

Cao,

Jiang,

Yan

et al. 2024

CNS Neurosci Ther

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AimsPaclitaxel (PTX) is extensively utilized in the management of diverse solid tumors, frequently resulting in paclitaxel‐induced peripheral neuropathy (PIPN). The present study aimed to investigate sex differences in the behavioral manifestations and underlying pathogenesis of PIPN and search for clinically efficacious interventions.MethodsMale and female C57BL/6 mice (5–6 weeks and 12 months, weighing 18–30 g) were intraperitoneally (i.p.) administered paclitaxel diluted in saline (NaCl 0.9%) at a dose of 2 mg/kg every other day for a total of 4 injections. Von Frey and hot plate tests were performed before and after administration to confirm the successful establishment of the PIPN model and also to evaluate the pain of PIPN and the analgesic effect of PD‐L1. On day 14 after PTX administration, PD‐L1 protein (10 ng/pc) was injected into the PIPN via the intrathecal (i.t.) route. To knock down TRPV1 in the spinal cord, adeno‐associated virus 9 (AAV9)‐Trpv1‐RNAi (5 μL, 1 × 1013 vg/mL) was slowly injected via the i.t. route. Four weeks after AAV9 delivery, the downregulation of TRPV1 expression was verified by immunofluorescence staining and Western blotting. The levels of PD‐L1, TRPV1 and CGRP were measured via Western blotting, RT–PCR, and immunofluorescence staining. The levels of TNF‐α and IL‐1β were measured via RT–PCR.ResultsTRPV1 and CGRP protein and mRNA levels were higher in the spinal cords of control female mice than in those of control male mice. PTX‐induced nociceptive behaviors in female PIPN mice were greater than those in male PIPN mice, as indicated by increased expression of TRPV1 and CGRP. The analgesic effects of PD‐L1 on mechanical hyperalgesia and thermal sensitivity were significantly greater in female mice than in male mice, with calculated relative therapeutic levels increasing by approximately 2.717‐fold and 2.303‐fold, respectively. PD‐L1 and CGRP were partly co‐localized with TRPV1 in the dorsal horn of the mouse spinal cord. The analgesic effect of PD‐L1 in PIPN mice was observed to be mediated through the downregulation of TRPV1 and CGRP expression following AAV9‐mediated spinal cord specific decreased TRPV1 expression.ConclusionsPTX‐induced nociceptive behaviors and the analgesic effect of PD‐L1 in PIPN mice were sexually dimorphic, highlighting the significance of incorporating sex as a crucial biological factor in forthcoming mechanistic studies of PIPN and providing insights for potential sex‐specific therapeutic approaches.

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7-Chloro-4-(Phenylselanyl) Quinoline Is a Novel Multitarget Therapy to Combat Peripheral Neuropathy and Comorbidities Induced by Paclitaxel in Mice

Cited by 6 publications

References 91 publications

New Treatment for the Cognitive and Emotional Deficits Linked with Paclitaxel-Induced Peripheral Neuropathy in Mice

New Treatment for the Cognitive and Emotional Deficits Linked with Paclitaxel-Induced Peripheral Neuropathy in Mice

The Antinociceptive Responses of MTDZ to Paclitaxel−Induced Peripheral Neuropathy and Acute Nociception in Mice: Behavioral, Pharmacological, and Biochemical Approaches

Sex differences in PD‐L1‐induced analgesia in paclitaxel‐induced peripheral neuropathy mice depend on TRPV1‐based inhibition of CGRP

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