Methylprednisolone inhibits the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans in reactivated astrocytes

Abstract

Reactive gliosis caused by post-traumatic injury often results in marked expression of chondroitin sulfate proteoglycan (CSPG), which inhibits neurite outgrowth and regeneration. Methylprednisolone (MP), a synthetic glucocorticoid, has been shown to have neuroprotective and anti-inflammatory effects for the treatment of acute spinal cord injury (SCI). However, the effect of MP on CSPG expression in reactive glial cells remains unclear. In our study, we induced astrocyte reactivation using alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and cyclothiazide to mimic the excitotoxic stimuli of SCI. The expression of glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivation, and CSPG neurocan and phosphacan were significantly elevated by AMPA treatment. The conditioned media from AMPA-treated astrocytes strongly inhibited neurite outgrowth of rat dorsal root ganglion neurons, and this effect was reversed by pretreatment with MP. Furthermore, MP downregulated GFAP and CSPG expression in adult rats with SCI. Additionally, both the glucocorticoid receptor (GR) antagonist RU486 and GR siRNA reversed the inhibitory effects of MP on GFAP and neurocan expression. Taken together, these results suggest that MP may improve neuronal repair and promote neurite outgrowth after excitotoxic insult via GR-mediated downregulation of astrocyte reactivation and inhibition of CSPG expression.

Prolactin Induces MAPK Signaling in Neural Progenitors without Alleviating Glucocorticoid-Induced Inhibition of in vitro Neurogenesis

“…Moreover, suppression of astroglial scar formation enhances axonal regeneration and functional recovery after spinal cord injury [42]. An anti-astroglial effect was also demonstrated for methylprednisolone, a synthetic glucocorticoid, inhibiting the expression of GFAP in reactivated astrocytes [43].…”

Curcumin Provides Neuroprotection After Spinal Cord Injury

“…Astrogliosis is a characteristic inflammatory reactive response of astrocytes after SCI. Reactive astrogliosis may impair axonal regeneration and functional neuronal recovery [6,9,16]. The expression of GFAP indicates hypertrophy and proliferation of astrocytes after neurological insults.…”

“…Currently, methylprednisolone is the only recognized therapy for SCI, and its neuroprotective effect appears to be mediated via the inhibition of inflammatory reactions and lipid peroxidation [16]. However, the therapeutic effect of methylprednisolone is relatively minor [6], and the side effects associated with methylprednisolone are significant, including gastrointestinal bleeding, gastritis, and Cushing's syndrome [17].…”

Duration of lipid peroxidation after acute spinal cord injury in rats and the effect of methylprednisolone

“…17,18,22,23,25,43 This in turn has been thought to result in preservation of neurons, axons, myelin, and intracellular organelles, including the mitochondria and nucleus. 30,31 However, more recent studies have suggested that methylprednisolone acts preferentially on glia and has less of an effect on neurons, 33 and seems to have a significant impact on glial activation, thereby reducing the production of inhibitory chondroitin sulfate proteoglycans 36 and possibly facilitating an environment more suitable for regeneration.…”