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Melatonin Plus Folic Acid Treatment Ameliorates Reserpine-Induced Fibromyalgia: An Evaluation of Pain, Oxidative Stress, and Inflammation

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Melatonin Plus Folic Acid Treatment Ameliorates Reserpine-Induced Fibromyalgia: An Evaluation of Pain, Oxidative Stress, and Inflammation

Roberta Fusco et al. Antioxidants (Basel).

Abstract

Background: Fibromyalgia is a chronic condition characterized by increased sensory perception of pain, neuropathic/neurodegenerative modifications, oxidative, and nitrosative stress. An appropriate therapy is hard to find, and the currently used treatments are able to target only one of these aspects.

Methods: The aim of this study is to investigate the beneficial effects of melatonin plus folic acid administration in a rat model of reserpine-induced fibromyalgia. Sprague-Dawley male rats were injected with 1 mg/kg of reserpine for three consecutive days and later administered with melatonin, folic acid, or both for twenty-one days.

Results: Administration of reserpine led to a significant decrease in the nociceptive threshold as well as a significant increase in depressive-like symptoms. These behavioral changes were accompanied by increased oxidative and nitrosative stress. Lipid peroxidation was significantly increased, as well as nitrotyrosine and PARP expression, while superoxide dismutase, nonprotein thiols, and catalase were significantly decreased. Endogenously produced oxidants species are responsible for mast cell infiltration, increased expression pro-inflammatory mediators, and microglia activation.

Conclusion: Melatonin plus acid folic administration is able to ameliorate the behavioral defects, oxidative and nitrosative stress, mast cell infiltration, inflammatory mediators overexpression, and microglia activation induced by reserpine injection with more efficacy than their separate administration.

Keywords: fibromyalgia; oxidative stress; pain.

Conflict of interest statement

The authors declare no conflict of interest

Figures

Figure 1
Figure 1
Efficacy of folic acid and melatonin administration on behavioral changes reserpine-induced. Behavioral tests: (A) Von Frey test, (B) hot plate test, (C) tail-flick test, (D) forced swimming test (D). A p-value < 0.05 was considered significant. * p < 0.05 vs. sham, ° p < 0.05 vs. vehicle, °° p < 0.01 vs. vehicle, *** p < 0.001 vs. sham, °°° p < 0.001 vs. vehicle.
Figure 2
Figure 2
Efficacy of folic acid and melatonin administration on oxidative stress reserpine-induced. (A) Estimation of lipid peroxidation, (B) estimation of non protein thiols, (C) estimation of superoxide dismutase, (D) estimation of catalase. A p-value < 0.05 was considered significant. ° p < 0.05 vs. vehicle, °° p < 0.01 vs. vehicle, *** p < 0.001 vs. sham, °°° p < 0.001 vs. vehicle.
Figure 3
Figure 3
Efficacy of folic acid and melatonin administration on nitrityrosine and PARP expression reserpine-induced. Immunohistochemistry evaluation of nitrityrosine expression in (A) sham, (B) vehicle, (C) folic acid, (D) melatonin, (E) melatonin plus folic acid and (F) graphical quantification. Immunohistochemistry evaluation of PARP expression in (G) sham, (H) vehicle, (I) folic acid, (L) melatonin, (M) melatonin plus folic acid, and (N) graphical quantification. A p-value < 0.05 was considered significant, °° p < 0.01 vs. vehicle, *** p < 0.001 vs. sham, °°° p < 0.001 vs. vehicle.
Figure 4
Figure 4
Efficacy of folic acid and melatonin administration on mast cells activation reserpine-induced. Evaluation of mast cell degranulation by toluidine blue in brain: (A) sham, (B) vehicle, (C) folic acid, (D) melatonin, (E) melatonin plus folic acid. Evaluation of mast cell degranulation by toluidine blue in sciatic nerve: (F) sham, (G) vehicle, (H) folic acid, (I) melatonin, (L) melatonin plus folic acid. 40× magnification is shown.
Figure 5
Figure 5
Efficacy of folic acid and melatonin administration on IL-1β, TNF-α, VEGF, and NGF expression reserpine-induced. Elisa kit of (A) IL-1β and (B) TNF-α levels. Western blots and respectively quantification of VEGF and NGF in (C) brain and (D) sciatic nerve. A p-value < 0.05 was considered significant. * p < 0.05 vs. sham, ° p < 0.05 vs. vehicle, ** p < 0.01 vs. sham, °° p < 0.01 vs. vehicle, *** p < 0.001 vs. sham, °°° p < 0.001 vs. vehicle.
Figure 6
Figure 6
Efficacy of folic acid and melatonin administration on Iba1 and CD11b expression reserpine-induced. Immunofluorescence of brain Iba1 in (A) sham, (B) vehicle, (C) folic acid, (D) melatonin, (E) melatonin plus folic acid. Immunofluorescence of brain CD11b in (F) sham, (G) vehicle, (H) folic acid, (I) melatonin, (L) melatonin plus folic acid. 40× magnification is shown.

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