Amifostine protects from the peripheral sensory neuropathy induced by oxaliplatin in mice

Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.

Subarachnoid injection of ifenprodil and ketamine association improves the anti-hyperalgesic action of ketamine in dogs / Injeção subaracnoidea da associação ifenprodil e cetamina melhora a ação anti-hiperalgésica da cetamina em cães

To test clinically whether a small dose of ifenprodil can enhance the anti-hyperalgesic effect of ketamine in dogs, a prospective randomized cross-over study was done with eight mongrel dogs (weighing 16.9 ± 3.7kg). Animals received two distinct treatments: ketamine (0.3mg kg-1; KT) and an ifenprodil plus ketamine combination (0.03mg kg-1 and 0.3mg kg-1, respectively; IKT). Dogs were anesthetized with propofol (5mg kg-1 intravenously) and a subarachnoid needle was placed between the 5th and 6th lumbar vertebrae. Five minutes after subarachnoid injection of KT or IKT, an incision including cutaneous and subcutaneous tissues was made on the common pad of one hind limb and was immediately closed with a simple interrupted suture pattern. The dogs were treated again 20 days later, using the contralateral pad and the opposite treatment. Sedation score (SS), lameness score (LS), heart rate (HR), respiratory rate (fR), and mechanical nociceptive threshold using von Frey filaments, were evaluated before anesthesia and at 1, 1.5, 2, 3, 4, 8, 12, and 24 hours after subarachnoid injection. There were no differences in SS, LS, HR or fR between treatments. The intensity of hyperalgesia was higher in KT than in IKT for 24 hours. The anti-hyperalgesic effect of IKT remained without statistical significant difference between 1 and 24 h. Prior subarachnoid administration of ifenprodil enhances the anti-hyperalgesic effect of subarachnoid ketamine in dogs. Ifenprodil can be co-administrated with ketamine to enhance its anti-hyperalgesic effect and to reduce acute post-incisional hyperalgesia without motor impairment and sedation.

Com a finalidade de testar se uma dose baixa de ifenprodil pode melhorar a ação anti-hiperalgésica da cetamina em cães, um estudo randomizado prospectivo no formato cross-over foi realizado em oito cães sem raça definida (pesando 16,9±3.7kg). Os animais receberam dois tratamentos distintos: cetamina (0,3mg kg-1; KT) e a associação de ifenprodil com cetamina (0,03mg kg-1 e 0,3mg kg-1, respectivamente; IKT). Os cães foram anestesiados com propofol (5mg kg-1, via intravenosa), e uma agulha subaracnoidea foi introduzida entre a quinta e sexta vértebras lombares. Após cinco minutos da injeção subaracnoidea de KT ou IKT, uma incisão abrangendo os tecidos cutâneo e subcutâneo foi realizada no coxim plantar comum de um dos membros pélvicos e imediatamente fechada com um padrão de sutura simples e interrompido. Os cães foram novamente tratados após 20 dias, usando-se o coxim plantar contralateral e o outro tratamento. Os escores de sedação (SS) e claudicação (LS); as frequências cardíacas (HR) e respiratória (fR) e o limiar nociceptivo ao estímulo mecânico, utilizando os filamentos de von Frey, foram avaliados antes da anestesia e uma, uma e meia; duas; três; quatro; oito; 12 e 24 horas após a injeção subaracnoidea. Não foram observadas diferenças significativas em SS, LS, HR ou na fR entre os tratamentos. A intensidade da hiperalgesia foi maior em KT que em IKT nas 24 horas. O efeito anti-hiperalgésico de IKT se manteve sem diferença significativa entre os tempos uma hora e 24 horas. A administração prévia de ifenprodil aumentou a ação anti-hiperalgésica da cetamina subaracnoidea em cães. O ifenprodil pode ser coadministrado com cetamina para aumentar seu efeito anti-hiperalgésico e reduzir a hiperlagesia aguda pós-incisional, sem alterações motoras e sedação.

Matrix metalloproteinase inhibitor COL-3 prevents the development of paclitaxel-induced hyperalgesia in mice

To study the potential of chemically modified tetracycline-3 [COL-3], a potent matrix metalloproteinase [MMP] inhibitor, to protect against the development of paclitaxel-induced painful neuropathy and its immunomodulatory effects. The reaction latency to thermal stimuli [hot plate test] of female BALB/c mice was recorded before and after treatment with paclitaxel [2 mg/kg i.p.], paclitaxel plus COL-3 [4, 20 or 40 mg/kg p.o.] or their vehicles for 5 consecutive days. Gene transcripts of CD11b [marker for microglia], 5 cytokines [IFN-gamma, IL-1 beta, IL-6, IL-10 and TNF- alpha] and 3 chemokines [CCL2, CXCL10 and CX3CL1] were quantified by real-time PCR in the brains, spinal cords and spleens of mice sacrificed on day 7 after treatment. Treatment with paclitaxel reduced the reaction latency time to thermal stimuli [thermal hyperalgesia] for 4 weeks, with maximum effect on days 7 and 10. The coadministration of paclitaxel with COL-3 40 mg/kg, but not lower doses, prevented the development of paclitaxel-induced thermal hyperalgesia. Treatment with paclitaxel alone or coadministration with COL-3 increased CD11b transcript levels in the brain but not in the spinal cord. Treatment with paclitaxel reduced IL-6 transcript levels in the spinal cord but did not alter the transcript levels of other cytokines or chemokines in the brain, spinal cord or spleen. The coadministration of COL-3 with paclitaxel significantly increased the transcript levels of IL-6 in the spleen and decreased CX3CL1 transcripts in the brain in comparison to treatment with paclitaxel alone. Our results indicate that the MMP inhibitor COL-3 protected against paclitaxel-induced thermal hyperalgesia and, thus, could be useful in the prevention of chemotherapy-induced painful neuropathy