Methylprednisolone Induces Neuro-Protective Effects via the Inhibition of A1 Astrocyte Activation in Traumatic Spinal Cord Injury Mouse Models

Abstract

Traumatic spinal cord injury (TSCI) leads to pathological changes such as inflammation, edema, and neuronal apoptosis. Methylprednisolone (MP) is a glucocorticoid that has a variety of beneficial effects, including decreasing inflammation and ischemic reaction, as well as inhibiting lipid peroxidation. However, the efficacy and mechanism of MP in TSCI therapy is yet to be deciphered. In the present study, MP significantly attenuated the apoptotic effects of H2O2 in neuronal cells. Western blot analysis demonstrated that the levels of apoptotic related proteins, Bax and cleaved caspase-3, were reduced while levels of anti-apoptotic Bcl-2 were increased. In vivo TUNEL assays further demonstrated that MP effectively protected neuronal cells from apoptosis after TSCI, and was consistent with in vitro studies. Furthermore, we demonstrated that MP could decrease expression levels of IBA1, Il-1α, TNFα, and C3 and suppress A1 neurotoxic reactive astrocyte activation in TSCI mouse models. Neurological function was evaluated using the Basso Mouse Scale (BMS) and Footprint Test. Results demonstrated that the neurological function of MP-treated injured mice was significantly increased. In conclusion, our study demonstrated that MP could attenuate astrocyte cell death, decrease microglia activation, suppress A1 astrocytes activation, and promote functional recovery after acute TSCI in mouse models.

GR‐α and GR‐β mRNA levels in peripheral blood mononuclear cells of acute myelitis patients can assist in the identification of glucocorticoid sensitivity and are correlated with glucocorticoid therapeutic effect

“…As expected, the improvement of spinal cord perception, pain sensation, and motor function was notably superior in the GC‐sensitive group to that in the GC‐refractory group after GC treatment. Much in line with our findings, GC methylprednisolone can effectively protect neurons from apoptosis after traumatic spinal cord injury and enhance neurological function in mice (Zou et al., 2021). Furthermore, we analyzed the correlation between GR‐α and GR‐β mRNA levels and spinal function after GC treatment.…”

“…Much in line with our findings, GC methylprednisolone can effectively protect neurons from apoptosis after traumatic F I G U R E 3 Correlation analysis between glucocorticoid receptor α (GR-α) and glucocorticoid receptor β (GR-β) mRNA and spinal function of acute myelitis (AM) patients treated with glucocorticoid (GC). The Pearson analysis method was used to analyze (a-c): the correlation between GR-α mRNA and spinal function score (sense of touch and pain, and motor functions) in AM patients; and (d-f): the correlation between GR-β mRNA and spinal function score spinal cord injury and enhance neurological function in mice (Zou et al, 2021). Furthermore, we analyzed the correlation between GR-α and GR-β mRNA levels and spinal function after GC treatment.…”

Intranasal Methylprednisolone Ameliorates Neuroinflammation Induced by Chronic Toluene Exposure

“…In the murine model of multiple sclerosis, we found that MP intranasally administered was able to reduce the inflammatory cytokines as well as the expression of activation markers of glia and astrocytes (Iba1 and GFAP, respectively) and improved the clinical score [27]. In this study, the treatment with only one dose of IN-MP significantly reduced some inflammatory features, such as TNF-α, ON, and astrocytes activation, results that are expected when potent anti-inflammatory drugs are employed [49]. Indeed, the damage induced by chronic exposure to toluene is partially reverted as soon as 24 h after IN-MP.…”

Regulatory Role of Mesenchymal Stem Cells on Secondary Inflammation in Spinal Cord Injury

“…83,84 A1 astrocytes strongly increase the expression of the classical complement cascade genes including complement component1s (C1s), C1r, C3, and C4, which were previously shown to be harmful to synapses, indicating that A1 astrocytes might be the "bad" player in neurological repair and remodeling. 85,86 In contrast, A2 astrocytes up-regulate the expression of neurotrophic factors and cytokines such as leukemia inhibitory factor, cardiotrophin-like cytokine factor 1, IL-10, and IL-6 to support neuronal restoration and survival, as well as synaptic repair, suggesting that A2 astrocytes might be the "good" players in neuroinflammation. [87][88][89] Therefore, differentiation of astrocytes into an A2 phenotype may facilitate functional recovery after SCI while inhibiting secondary inflammation-mediated damage.…”