Melatonin improves functional recovery in female rats after acute spinal cord injury by modulating polarization of spinal microglial/macrophages

Abstract

Spinal cord injury (SCI) is a devastating neurological disorder, but few drugs have proven to be effective for its treatment. Neuroinflammation exaggerates the secondary injury subsequent to trauma. Emerging evidence suggests that melatonin may help protect neural tissue against secondary injury after SCI, but the underlying mechanisms remain elusive. Microglial/macrophages polarization plays an important role in regulating immune responses. To examine whether melatonin exerts neuroprotective effects after acute SCI by regulating microglial/macrophages polarization in the spinal cord, we administered intraperitoneal injections of melatonin (50 mg/kg) in female rats immediately after SCI and then daily for seven consecutive days (n = 6). Compared with the vehicle‐treated group (n = 6), the melatonin‐treated group exhibited a greater Basso, Beattie, and Bresnahan locomotor rating score, smaller spinal cavity, and less cleaved caspase 3 immunofluorescence staining in the injured spinal segments. Real‐time PCR data revealed decreases in the expression levels of M1 microglia phenotypic markers and increases in M2 markers in the spinal cord of melatonin‐treated SCI rats, as compared to levels in the vehicle‐treated group. Melatonin increased the number of CD206+ and Arg1+ cells, decreased the number of CD16+ and iNOS+ cells and reduced the levels of pro‐inflammatory cytokines (TNF‐α, IL‐6, and IL‐1β) in the spinal cord tissue of female SCI rats. Current findings suggest that melatonin may inhibit pro‐inflammatory responses and promote M2 polarization of microglial/macrophages in the spinal cord in the early stage of SCI, facilitating functional recovery. Accordingly, melatonin may represent a promising therapeutic candidate for acute SCI.

Modulation of inflammatory factors predicts the outcome following spinal cord injury

“…F4/80 is a definite marker of macrophages [28]. iNOS indicates that macrophages polarize to M1 and Arg1 indicates that macrophages polarize to M2 [29]. NF200 is a specific marker of axonal regeneration.…”

Modulation of inflammatory factors predicts the outcome following spinal cord injury

“…F4/80 is a de nite marker of macrophages [32]. iNOS indicates that macrophages polarize to M1 and Arg1 indicates that macrophages polarize to M2 [33]. NF200 is a skeletal structure of neural cells and axons,a speci c marker of axonal regeneration, which can re ect the degree of axonal regeneration in the spinal cord of rats after SCI [34].…”

Bee venom acupuncture reduces neuroinflammation modulating microglia/macrophage phenotype polarization in spinal cord injury compression model

“…In the acute phase of the inflammatory response following SCI, M1 polarization phenotype markers are prevalent and pro-inflammatory factors such as IL1β, IL-6, TNF-α and iNOS contributing to positive feedback that triggers an exaggerated inflammatory response causing greater tissue damage around the SCI area [22,25] . However, the response generated by M1 status can be modulated by the M2 polarization phenotype that secretes anti-inflammatory factors such as IL-10, IL13, TGF-β and Arginase-1 (Arg-1) [18,27,34] .…”

“…The profile of microglia/macrophage polarization phenotypes in M1/M2 are initially simplified paradigms in an attempt to understand the complexity of the inflammatory response [22,25] , in which M1 is described for presenting a pro-inflammatory profile, by stimulating and secreting inflammatory factors such as iNOS, IL-1β, TNF-α; whereas M2 presents anti-inflammatory profile by promoting the release of antiinflammatory cytokines such as IL-10, phagocyte myelin remnants and inhibiting factors to tissue regeneration [18,23,25,27,28] . After SCI, there seems to be a dominance of the M1 phenotype [25,27] , and although more recent studies have shown that microglia can have multiple activation phenotypes (a "full spectrum of activation") and consider the model of two dualistic microglial state is too simplistic for revision [22] ; therapeutic approaches that stimulate greater phenotypic polarization of microglia/macrophages in the M2 profile are likely to represent a promising tool [18,23,25] .…”