RESUMO
The multicomponent etiology, complex clinical implications, dose-based side effect and degree of pain mitigation associated with the current pharmacological therapy is incapable in complete resolution of chronic neuropathic pain patients which necessitates the perpetual requirement of novel medication therapy. Therefore, this study explored the ameliorative aptitude of two novel methanimine imitative like (E)-N-(4-nitrobenzylidene)-4chloro-2-iodobenzamine (KB 09) and (E)-N-(4-methylbenzylidene)-4chloro-2-iodobenzamine (KB 10) in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rat model. Standard behavioral tests like dynamic and static allodynia, cold, thermal and mechanical hyperalgesia along with rotarod activity were performed at various experimental days like 0, 3, 7, 14 and 21. Enzyme linked immunosorbent assay (ELISA) on spinal tissue and antioxidant assays on sciatic nerve were executed accompanied by molecular docking and simulation studies. Prolonged ligation of sciatic nerve expressively induced hyperalgesia as well as allodynia in rats. KB 09 and KB 10 substantially attenuated the CCI elicited hyperalgesia and allodynia. They significantly reduced the biomarkers of pain and inflammation like Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in ELISA and while enhanced the GSH, SOD and CAT and diminished the MDA levels during antioxidant assays. KB 09 displayed -9.62 kcal/mol with TNF-α and -7.68 kcal/mol binding energy with IL-6 whereas KB 10 exhibited binding energy of -8.20 kcal/mol with IL-6 while -11.68 kcal/mol with TNF-α and hence both trial compounds ensured stable interaction with IL-6 and TNF-α during computational analysis. The results advocated that both methanimine derivatives might be novel candidates for attenuation of CCI-induced neuropathic pain prospects via anti-nociceptive, anti-inflammatory and antioxidant mechanisms.
Assuntos
Hiperalgesia , Simulação de Acoplamento Molecular , Neuralgia , Nervo Isquiático , Animais , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Masculino , Hiperalgesia/tratamento farmacológico , Nervo Isquiático/lesões , Nervo Isquiático/efeitos dos fármacos , Ratos , Ratos Wistar , Modelos Animais de Doenças , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos/química , Antioxidantes/farmacologia , Antioxidantes/química , Simulação por Computador , Constrição , Iminas/química , Iminas/farmacologiaRESUMO
Vincristine induced peripheral neuropathy (VIPN) is a serious untoward side effect suffered by cancer patients, which still lacks an adequate therapeutic approach. This study examined the alleviating potential of novel methanimine derivatives i.e. (E)-N-(4-nitrobenzylidene)-4-chloro-2-iodobenzamine (KB 9) and (E)-N-(2-methylbenzylidene)-4-chloro-2-iodobenzamine (KB 10) in VIPN. Vincristine was injected in BALB/c mice for 10 days to instigate nociceptive neuropathy. Dynamic and static allodynia, thermal (hot and cold) hyperalgesia were evaluated at 0, 5, 10 and 14 days using cotton brush, Von Frey filament application, hot plate test, acetone drop and cold water respectively. Tumour necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), lipid peroxide (LPO), glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD) and reactive oxygen species (ROS) assays were performed to assess the efficacy of KB9 and KB10 against neuroinflammation and oxidative stress utilizing ELISA, immunohistochemistry and western blot analysis in brain and sciatic nerve tissues. Computational studies were executed to determine the stable binding conformation of both compounds with respect to COX-2 and NF-κB. Interestingly, both compounds substantially reduced protein expression related to neuroinflammation, oxidative stress (LPO, GST, SOD, CAT) and pain (NF-κB, COX-2, IL-1ß and TNF-α). This molecular analysis suggested that the neuroprotective effect of KB9 and KB10 was mediated via regulation of inflammatory signaling pathways. Overall, this study demonstrated that KB9 and KB10 ameliorated vincristine induced neuropathy, through anti-inflammatory, anti-nociceptive and antioxidant mechanisms.
Assuntos
Fármacos Neuroprotetores , Doenças do Sistema Nervoso Periférico , Camundongos , Animais , Vincristina/farmacologia , Catalase/metabolismo , Antioxidantes/uso terapêutico , Interleucina-1beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Espécies Reativas de Oxigênio , Fármacos Neuroprotetores/farmacologia , NF-kappa B/metabolismo , Ciclo-Oxigenase 2/metabolismo , Peróxidos Lipídicos/farmacologia , Acetona/farmacologia , Acetona/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/patologia , Estresse Oxidativo , Hiperalgesia/tratamento farmacológico , Superóxido Dismutase/metabolismo , Glutationa/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Água , Transferases/metabolismo , Transferases/farmacologia , Transferases/uso terapêuticoRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is an increasingly important problem for cancer survivors and is the foremost cause of drug-induced morbidity. In this study, the antinociceptive efficacy of salicylidene salicylhydrazide (SSH) in CIPN was investigated. SSH was evaluated for acute toxicity, antinociceptive effectiveness against tonic and phasic pain modalities, anti-inflammatory propensity, and effect on motoric balance. SSH was tested in the mouse models of oxaliplatin, paclitaxel, and vincristine associated established neuropathic nociceptive paradigms. The tested doses of SSH (10-75 mg/kg) strongly suppressed the expression of acetic acid-induced tonic visceral nociception, formalin-induced biphasic nociception, and acute phasic thermal nociception. SSH selectively antagonized the capsaicin-elicited nociceptive behavior. SSH produced a significant reduction in the phlogistic agents-induced temporal inflammatory escalation involving prostaglandins, serotonin, and histamine. SSH was devoid of any adverse-effects that impair the neurological processes involved in the arousal and coordination of movements. The neuropathic nociception inflicted by chemotherapeutic agents were expressed as reduced sensitivity to non-noxious mechanical stimuli (mechanical allodynia), increased nociceptive response to cold (cold allodynia), and decreased nociceptive latency to heat (heat hyperalgesia). SSH (50 and 75 mg/kg) significantly suppressed the expression of CIPN-induced established neuropathic allodynia and hyperalgesia and the anti-neuropathic effects were equipotent to gabapentin. These findings concluded that SSH is a novel analgesic that can be useful for treating peripheral neuropathic pain conditions linked with chemotherapy with the advantage of being free of neurological adverse-effects encountered with gabapentinoids.
Assuntos
Antineoplásicos/toxicidade , Benzaldeídos/uso terapêutico , Hidrazonas/uso terapêutico , Medição da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Benzaldeídos/química , Benzaldeídos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Hidrazonas/química , Hidrazonas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Medição da Dor/métodos , Doenças do Sistema Nervoso Periférico/metabolismoRESUMO
The present study was conducted to synthesize nitrogen containing derivatives of salicyl alcohol and to investigate in vivo their ulcerogenic potential in comparison with aspirin in rats. The compounds [4-(2-hydroxybenzyl) morpholin-4-iumchloride (I)] and [1,4-bis(2-hydroxybenzyl) piperazine-1,4-diium chloride (II)] were synthesized and their chemical structures were characterized using spectral data. In our previous study (Ali et al., Afr J Pharm Pharmacol 7:585-596, 2013), both compounds showed anti-inflammatory, antinociceptive, and antipyretic properties in standard animal models and a greater binding affinity for cyclooxygenase-2 versus cyclooxygenase-1 in molecular docking and dynamics analysis. For in vivo studies, animals were randomly divided into four groups. The synthetic compounds (both at 100 or 150 mg/kg), aspirin (150 mg/kg), or saline vehicle was administered orally, once daily for 6 days and then tested for ulcerogenic activity. At the end of the procedure, gastric juice and tissues were collected and subjected to biochemical and histological analyses. The results of the study revealed that in the case of the aspirin-treated group, there was a significant increase in gastric juice volume, free acidity, total acidity, and ulcer score and a decrease in gastric pH. Moreover, histological examination of the gastric mucosa of the aspirin-treated group indicated morphological changes while neither of the synthetic compounds showed any significant ulcerogenic or cytotoxic properties. The results of the present study suggest that both compounds are free from ulcerogenic side effects and may represent a better alternative to aspirin.