Therapeutic efficacy of cyclosporin A against spinal cord injury in rats with hyperglycemia

Abstract

The present study aimed to explore the therapeutic effects of cyclosporin A (CsA) on spinal cord injury (SCI) in rats with hyperglycemia and to identify a novel potential method to treat SCI in the presence of hyperglycemia. Female Sprague-Dawley (SD) rats were randomly allocated into four groups: Sham, SCI, SCI+hyperglycemia and SCI+hyperglycemia+CsA groups. Streptozotocin-induced hyperglycemic SD rats and a weight-drop contusion SCI model were established. The Basso, Beattie, Bresnahan scale and inclined plane test were used to evaluate the neurological function of the rats. Flow cytometric assay was performed to detect the apoptotic rates of cells in the spinal cord. ELISA and western blot analysis were performed to determine the levels of interleukin (IL)-10, tumor necrosis factor (TNF)-α, cyclophilin-D (Cyp-D) and apoptosis-inducing factor (AIF). The results demonstrated that CsA significantly improved the neurological function of the SCI rats with hyperglycemia. CsA markedly reduced the number of apoptotic cells exaggerated by hyperglycemia in the spinal cord of the SCI rats. CsA significantly decreased the expression levels of IL-10, TNF-α, Cyp-D and AIF in the spinal cord of the SCI rats. Overall, the present study revealed a significant role of CsA in the treatment of SCI in the presence of hyperglycemia by inhibiting the apoptosis of spinal cord cells.

Effects of Cyclosporin-A, Minocycline, and Tacrolimus (FK506) on Enhanced Behavioral and Biochemical Recovery from Spinal Cord Injury in Rats

“…The drugs were effective in the order FK506 > minocycline > CsA throughout. Earlier studies have also used BBB scoring along with other behavioral parameters and have shown significant behavioral functional outcome in the SCI animals treated with FK506 [7,22,60,67,69,70,74,76], minocycline [22,28,[43][44][45], and CsA [18,52,53,58,61]. In addition to the therapeutic effects of the three drugs, it has been also suggested that the daily routine behavioral assessment procedures may also assist the animals as equivalent to their exercises that help them to recover from SCI [107].…”

“…CsA has also been reviewed and reported as a potent neuroprotectant for functional recovery from SCI [5,55]. The significant protective role of CsA has been reported for recovery from SCI through inhibiting the apoptosis of spinal cord cells [53], improving locomotor function [58], increasing mean arterial pressure [110], inhibiting NOS [56], diminishing demyelination and neuronal cell death [60], attenuating reactive astrocytosis due to injury improved neurologic outcome [50], and reducing pain [111].…”

“…Cyclosporin-A is an immunosuppressive cyclic undecapeptide that inhibits T cells and depresses both cellular and humoral immune responses to prevent graft rejection and reduces the inflammatory responses [52]. CsA significantly decreases the expression levels of interleukin-10, tumor necrosis factor-α, cyclophilin-D (Cyp-D), and apoptosis-inducing factor (AIF) [53]. CsA does not readily cross the blood-spinal cord barrier (BSCB), which restricts the clinical application of CsA for SCI treatment.…”

“…CsA may also induce other non-immunological effects that could be beneficial for treatment of neurological disorders [57]. CsA has been widely used in the treatment of various diseases including aplastic anemia, nephritic syndrome, rheumatoid arthritis, psoriasis, and cerebral ischemic injuries [53]. CsA promotes neuroprotection by diminishing both demyelination and neuronal cell death, resulting in a better motor outcome after SCI [52,58,59].…”

Trends in Neuroprotective Strategies after Spinal Cord Injury: State of the Art

“…CsA inhibits T-helper lymphocytes, cytotoxic and inflammatory responses in macrophages, inducible nitric oxide synthase (iNOs) expression avoiding the formation of nitric oxide (NO)-derived cytotoxic species, Cox-2 mRNA accumulation, tumor necrosis factor (TNFα) production and reduces cytokines and interleukins production (IL-1, IL-2, and IL-6). Also, CsA reduced the apoptosis of SC cells and increased the protein expression levels of cyclophilin-D (Cyp-D) and apoptosis-inducing factor (AIF) [61,62]. This compound is capable of inducing motor recovery after SCI [63].…”