Spine-Adjusting Instrument (Impulse®) Attenuates Nociception and Modulates Oxidative Stress Markers in the Spinal Cord and Sciatic Nerve of a Rat Model of Neuropathic Pain.

OBJECTIVE: Oxidative stress plays an important role in neuropathic pain (NP). Spinal manipulative therapy (SMT) can exert beneficial effects on pain outcomes in humans and in animal models. SMT can also modulate oxidative stress markers in both humans and animals. We aimed to determine the effect of Impulse®-assisted SMT (ISMT) on nociception and oxidative stress biomarkers in the spinal cords and sciatic nerves of rats with NP. METHODS: NP was induced by chronic constriction injury (CCI) of the sciatic nerve. Animals were randomly assigned to naive, sham (rats with sciatic nerve exposure but without ligatures), or CCI, with and without ISMT. ISMT was applied onto the skin area corresponding to the spinous process of L4-L5, three times per week for 2 weeks. Mechanical threshold, latency to paw withdrawal in response to thermal stimulus, and oxidative stress biomarkers in the spinal cord and sciatic nerve were the main outcomes evaluated. RESULTS: ISMT significantly increased mechanical threshold and withdrawal latency after CCI. In the spinal cord, ISMT prevented the increase of pro-oxidative superoxide anion generation and hydrogen peroxide levels. Lipid hydroperoxide levels both in the spinal cord and in the sciatic nerve were attenuated by ISMT. Total antioxidant capacity increased in the spinal cords and sciatic nerves of CCI rats with and without ISMT. CCI and ISMT did not significantly change the total thiol content of the spinal cord. CONCLUSIONS: Our findings suggest that reduced oxidative stress in the spinal cord and/or nerve may be an important mechanism underlying a therapeutic effect of SMT to manage NP nonpharmacologically.

Acute exercise stimulates macrophage function: possible role of NF-kappaB pathways.

Moderate physical activity when performed on a regular basis presents a number of benefits to the whole organism, especially regarding immune system function, such as augmenting resistance to infections and to cancer growth. Although glutamine production by active muscle cells as well as neuroendocrine alterations mediated by the chronic adaptation to exercise may play a role, the entire mechanism by which exercise makes the immune system aware of challenges remains mostly uncovered. This is particularly true for the effects of an acute exercise session on immune function. In this work, circulating monocytes/macrophages from sedentary rats submitted to an acute (1 h) swimming session were tested for the ability of phagocytosing zymosan particles, phorbol myristate acetate (PMA)-induced hydrogen peroxide production, nitric oxide (NO) release (assessed by nitrate and nitrite production) and the expression of NO synthases (NOS-1, NOS-2 and NOS-3). The results showed that an exercise bout induced a 2.4-fold rise in macrophage phagocytic capacity (p = 0.0041), a 9.6-fold elevation in PMA-induced hydrogen peroxide release into the incubation media (1-h, p = 0.0022) and a 95.5%-augmentation in nitrite basal production (1-h incubation; p = 0.0220), which was associated with a marked expression of NOS-2 (the inducible NOS isoform; p = 0.0319), but not in other NOS gene products. Although NOS-2 expression is nuclear factor-kappaB (NF-kappaB)-dependent, no systemic oxidative stress was found, as inferred from the data of plasma TBARS and glutathione disulphide (GSSG) to glutathione (GSH) ratio in circulating blood erythrocytes which remained constant after the acute exercise. Also, no stressful situation seemed to be faced by monocytes/macrophages, since the expression of the 70-kDa heat shock protein (HSP70) remained unchanged. We conclude that NF-kappaB-dependent induction of NOS-2 and macrophage activation must be related to local factor(s) produced in the surroundings of monocytes/macrophages.

MRP1/GS-X pump ATPase expression: is this the explanation for the cytoprotection of the heart against oxidative stress-induced redox imbalance in comparison to skeletal muscle cells?

Striated muscle activity is always accompanied by oxidative stress (OxStress): the more intense muscle work and/or its duration, the more a redox imbalance may be attained. In spite of cardiac muscle functioning continuously, it is well known that the heart does not suffer from OxStress-induced damage over a broad physiological range. Although the expression of antioxidant enzymes may be of importance in defending heart muscle against OxStress, a series of combined antioxidant therapeutic approaches have proved to be mostly ineffective in avoiding cellular injury. Hence, additional mechanisms may be involved in heart cytoprotection other than antioxidant enzyme activities. The strong cardiotoxic effect of doxorubicin-induced cancer chemotherapy shed light on the possible role for multidrug resistance-associated proteins (MRP) in this context. Muscle activity-induced 'physiological' OxStress enhances the production of glutathione disulfide (GSSG) thus increasing the ratio of GSSG to glutathione (GSH) content inside the cells, which, in turn, leads to redox imbalance. Since MRP1 gene product (a GS-X pump ATPase) is a physiological GSSG transporter, adult Wistar rats were tested for MRP1 expression and activity in the heart and skeletal muscle (gastrocnemius), in as much as the latter is known to be extremely sensitive to muscle activity-induced OxS. MRP1 expression was completely absent in skeletal muscle. In contrast, the heart showed an exercise training-dependent induction of MRP1 protein expression which was further augmented (2.4-fold) as trained rats were challenged with a session of acute exercise. On the other hand, inducible expression of the 70-kDa heat shock protein (HSP70), a universal marker of cellular stress, was completely absent in the heart of sedentary and acutely exercised rats, whereas skeletal muscle showed a conspicuous exercise-dependent HSP70 expression, which decreased by 45% with exercise training. This effect was paralleled by a 58% decrease in GSH content in skeletal muscle which was even higher (an 80%-fall) after training thus leading to a marked redox imbalance ([GSSG]/[GSH] raised up to 38-fold). In the heart, GSH contents and [GSSG]/[GSH] ratio remained virtually unchanged even after exercise challenges, while GS-X pump activity was found to be 20% higher in the heart related to skeletal muscle. These findings suggest that an intrinsic higher capacity to express the MRP1/GS-X pump may dictate the redox status in the heart muscle thus protecting myocardium by preventing GSSG accumulation in cardiomyocytes as compared to skeletal muscle fibres.