Spinal cord stimulation attenuates paclitaxel-induced gait impairment and mechanical hypersensitivity via peripheral neuroprotective mechanisms in tumor-bearing rats.

BACKGROUND: Taxanes such as paclitaxel (PTX) induce dose-dependent chemotherapy-induced peripheral neuropathy (CIPN), which is associated with debilitating chronic pain and gait impairment. Increased macrophage-related proinflammatory activities have been reported to mediate the development and maintenance of neuropathic pain. While spinal cord stimulation (SCS) has been used for a number of pain conditions, the mechanisms supporting its use for CIPN remain to be elucidated. Thus, we aimed to examine whether SCS can attenuate Schwann cell-mediated and macrophage-mediated neuroinflammation in the sciatic nerve of Rowlette Nude (RNU) rats with PTX-induced gait impairment and mechanical hypersensitivity. METHODS: Adult male tumor-bearing RNU rats were used for this study examining PTX treatment and SCS. Gait and mechanical hypersensitivity were assessed weekly. Cytokines, gene expression, macrophage infiltration and polarization, nerve morphology and Schwann cells were examined in sciatic nerves using multiplex immunoassay, bulk RNA sequencing, histochemistry and immunohistochemistry techniques. RESULTS: SCS (50 Hz, 0.2 milliseconds, 80% motor threshold) attenuated the development of mechanical hypersensitivity (20.93±0.80 vs 12.23±2.71 grams, p<0.0096) and temporal gait impairment [swing (90.41±7.03 vs 117.27±9.71%, p<0.0076), and single stance times (94.92±3.62 vs 112.75±7.27%, p<0.0245)] induced by PTX (SCS+PTX+Tumor vs Sham SCS+PTX+Tumor). SCS also attenuated the reduction in Schwann cells, myelin thickness and increased the concentration of anti-inflammatory cytokine interleukin (IL)-10. Bulk RNA sequencing revealed differential gene expression after SCS, with 607 (59.2%) genes upregulated while 418 (40.8%) genes were downregulated. Notably, genes related to anti-inflammatory cytokines and neuronal growth were upregulated, while genes related to proinflammatory-promoting genes, increased M2γ polarization and decreased macrophage infiltration and Schwann cell loss were downregulated. CONCLUSION: SCS may attenuate PTX-induced pain and temporal gait impairment, which may be partly attributed to decreases in Schwann cell loss and macrophage-mediated neuroinflammation in sciatic nerves.

Synergistic interaction between acetaminophen and L-carnosine improved neuropathic pain via NF-κB pathway and antioxidant properties in chronic constriction injury model.

Background: Inflammation is known to underlie the pathogenesis in neuropathic pain. This study investigated the anti-inflammatory and neuroprotective mechanisms involved in antinociceptive effects of co-administration of acetaminophen and L-carnosine in chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats. Methods: Fifty-six male Wistar rats were randomly divided into seven experimental groups (n = 8) treated with normal saline/acetaminophen/acetaminophen + L-carnosine. CCI was used to induce neuropathic pain in rats. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests, respectively. Investigation of spinal proinflammatory cytokines and antioxidant system were carried out after twenty-one days of treatment. Results: The results showed that the co-administration of acetaminophen and L-carnosine significantly (P < 0.001) increased the paw withdrawal threshold to thermal and mechanical stimuli in ligated rats compared to the ligated naïve group. There was a significant (P < 0.001) decrease in the levels of nuclear factor kappa light chain enhancer B cell inhibitor, calcium ion, interleukin-1-beta, and tumour necrotic factor-alpha in the spinal cord of the group coadministered with acetaminophen and L-carnosine compared to the ligated control group. Co-administration with acetaminophen and L-carnosine increased the antioxidant enzymatic activities and reduced the lipid peroxidation in the spinal cord. Conclusions: Co-administration of acetaminophen and L-carnosine has anti-inflammatory effects as a mechanism that mediate its antinociceptive effects in CCI-induced peripheral neuropathy in Wistar rat.

Effects of co-administration of vitamin E and lithium chloride on chronic constriction injury-induced neuropathy in male Wistar rats: Focus on antioxidant and anti-inflammatory mechanisms.

OBJECTIVES: This study investigated the antinociceptive effects of co-administration of lithium chloride (LiCl) and vitamin E (Vit E) on chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats. It further explored the anti-inflammatory and neuroprotective properties of LiCl and Vit E, which may be complementary to the antinociceptive effects of the two substances. METHODS: Thirty-six male Wistar rats, 190.00 ± 10.00 g of body weight were randomly assigned to 6 experimental groups and administered with normal saline, Vit E, LiCl, or their combination, once daily for 21 days. CCI was used to induce neuropathic pain (NP) and mechanical allodynia was assessed using von Frey filaments and pinprick test. Open field maze (OFM) was used to assess the exploratory behavior. Biochemical parameters were assessed in the dorsal root ganglion after 21 days of treatment. RESULTS: Mechanical allodynia was developed in rats following CCI. Co-administration of LiCl and Vit E synergistically reduced mechanical hyperalgesia in rats which were significantly different compared with the single administration of either Vit E or LiCl. Combined doses of Vit E and LiCl significantly increases the explorative behavior in the OFM. CCI increased malondialdehyde (MDA), tumor necrotic factor-alpha (TNF-α), calcitonin gene-related polypeptide, calcium ion (Ca2+ ), and reduced superoxide dismutase (SOD) activities. Co-administration of LiCl and Vit E significantly reduced MDA, TNF-α, but increased SOD compared with ligated control. DISCUSSION: The findings revealed that the synergistic effects of the co-administration of Vit E and LiCl in ameliorating NP are mediated by their anti-inflammatory and antioxidant properties.

Antinociceptive effects of lead acetate in sciatic nerve chronic constriction injury model of peripheral neuropathy in male Wistar rats.

The toxicological effects of lead and its compounds have overshadowed its possible health beneficial effects. Currently, the success rate for treating neuropathic pain has been very low. This study investigated the antinociceptive effects of orally administered low dose lead acetate in sciatic nerve ligated Wistar rats. Thirty Wistar rats randomly divided into five groups were used for this study. Chronic constriction injury (CCI) was used to induce neuropathic pain in Wistar rats. Allodynic and hyperalgesic signs were investigated using von Frey filaments and hotplate, respectively. Morris water maze test was used to assess the memory functions of the rats. The study revealed that oral administration of low-dose lead acetate significantly (p < 0.05) increased pain thresholds of ligated rats. CCI enhanced memory function in Wistar rats which was significantly decreased following lead acetate administration. The findings suggest that lead acetate possesses antinociceptive effects in peripherally induced neuropathic pain model in Wistar rats.

Antinociceptive and neuroprotective effects of bromelain in chronic constriction injury-induced neuropathic pain in Wistar rats.

BACKGROUND: The continuous search for a novel neuropathic pain drug with few or no side effects has been a main focus of researchers for decades. This study investigated the antinociceptive and neuroprotective effects of bromelain in sciatic nerve ligation-induced neuropathic pain in Wistar rats. METHODS: Forty-eight Wistar rats randomly divided into eight groups comprised of six animals each were used for this study. Peripheral neuropathy was induced via chronic constriction of the common sciatic nerve. Thermal hyperalgesic and mechanical allodynia were assessed using a hotplate and von Frey filaments, respectively. The functional recovery and structural architecture of the ligated sciatic nerve were evaluated using the sciatic functional index test and a histological examination of the transverse section of the sciatic nerve. The neuroprotective effects of bromelain were investigated in the proximal sciatic nerve tissue after 21 days of treatment. RESULTS: Bromelain significantly (P < 0.05) attenuated both the thermal hyperalgesia and mechanical allodynic indices of neuropathic pain. There were improvements in sciatic function and structural integrity in rats treated with bromelain. These rats showed significant (P < 0.05) increases in sciatic nerve nuclear transcription factors (nuclear factor erythroid-derived-2-related factors-1 [NrF-1] and NrF-2), antioxidant enzymes (superoxide dismutase and glutathione), and reduced membrane-lipid peroxidation compared with the ligated control group. CONCLUSIONS: This study suggest that bromelain mitigated neuropathic pain by enhancing the activities of nuclear transcription factors (NrF-1 and NrF-2) which increases the antioxidant defense system that abolish neuronal stress and structural disorganization.

Bromelain reversed electrolyte imbalance in the chronically constricted sciatic nerve of Wistar rats.

Derangement of electrolyte in the sensory nervous system has been attributed to the development and maintenance of hyperalgesic and allodynic symptoms in painful neuropathy. This study investigated the effect of bromelain on electrolyte imbalance in chronically constricted sciatic nerve of rats (a model of neuropathic pain). Forty Wistar rats, divided into five groups of eight animals each were used for this study. von Frey filaments, tail immersion and acetone spray tests were used to assessed allodynic and thermal hyperalgesic symptoms in the Wistar rats. Sodium ion (Na+), potassium ion (K+), calcium ion (Ca2+) and chloride ion (Cl-) concentrations as well as sodium-potassium and calcium electrogenic pump (Na-K ATPase and Ca ATPase, respectively) activities were estimated using spectrophotometry techniques. Bromelain significantly (p < 0.05) reversed elevation of Na+ and Ca2+ concentration compared with sciatic nerve chronic constriction injury (snCCI) group (35.68 ± 1.71 vs 44.46 ± 1.24 mg/ml/mg protein and 1.06 ± 0.19 vs 6.66 ± 0.03 mg/ml/mg protein, respectively). There were also significant (p < 0.05) increases in the level of K+ (0.84 ± 0.02 vs 0.36 ± 0.05 mg/ml/mg protein) and Cl- (18.51 ± 0.29 vs 15.82 ± 0.21 mg/ml/mg protein). Bromelain reduced the activities of Ca2+ electrogenic pumps significantly compared with snCCI. This study therefore suggests that bromelain mitigated electrolyte imbalance in chronic constricted injury of the sciatic nerve implying that this may be an important mechanism for the anti-nociceptive effect of bromelain.