Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model

Abstract

Calpain activation has been implicated in various pathologies, including neurodegeneration. Thus, calpain inhibition could effectively prevent spinal cord injury (SCI) associated with neurodegeneration. In the current study, a dog SCI model was used to evaluate the therapeutic potential of a selective calpain inhibitor (PD150606) in combination with methylprednisolone sodium succinate (MPSS) as an anti-inflammatory drug. SCI was experimentally induced in sixteen mongrel dogs through an epidural balloon compression technique. The dogs were allocated randomly into four groups: control, MPSS, PD150606, and MPSS+PD150606. Clinical evaluation, serum biochemical, somatosensory evoked potentials, histopathological, and immunoblotting analyses were performed to assess treated dogs during the study. The current findings revealed that the combined administration of MPSS+PD150606 demonstrated considerably lower neuronal loss and microglial cell infiltration than the other groups, with a significant improvement in the locomotor score. The increased levels of inflammatory markers (GFAP and CD11) and calcium-binding proteins (Iba1 and S100) were significantly reduced in the combination group and to a lesser extent in MPSS or PD150606 treatment alone. Interestingly, the combined treatment effectively inhibited the calcium-induced cleavage of p35, limited cdk5 activation, and inhibited tau phosphorylation. These results suggest that early MPSS+PD150606 therapy after acute SCI may prevent subsequent neurodegeneration via calpain inhibition.

Overexpression of the X-Linked Inhibitor of Apoptosis Protein (XIAP) in Neurons Improves Cell Survival and the Functional Outcome after Traumatic Spinal Cord Injury

“…As observed with the endogenous XIAP in WT animals (see Figure 1, and Keane and colleagues, 2001 [19]), the levels of uncleaved hXIAP protein dropped in the transgenic mice during the first days after injury in CB57hXIAP+ mice. Similar reductions were observed after neonatal hypoxia-ischemia in these transgenic mice [22], which may result from XIAP cleavage by caspases [18,19], Omi/HtrA2 [25], calpains [29], or the inflammasome [30]-which are also activated or overexpressed after SCI-or due to the loss of neurons expressing XIAP after SCI. These results demonstrate that locomotor improvements found after SCI were derived from the neuronal overexpression of XIAP and resulted, at least in part, from the inhibition of caspase cleavage by XIAP.…”

Overexpression of the X-linked Inhibitor of Apoptosis Protein (XIAP) in Neurons Improves Cell Survival and the Functional Outcome after Traumatic Spinal Cord Injury

“…As observed with the endogenous XIAP in WT animals (see Figure 1, and Keane and colleagues, 2001 [36]), the levels of uncleaved hXIAP protein drop in the transgenic mice during the first days after injury in CB57hXIAP+ mice. Similar reductions were observed after neonatal hypoxia-ischemia in these transgenic mice [38] which may result from XIAP cleavage by caspases [35,36], Omi/HtrA2 [41], calpains [45], or the inflammasome [46], which are also activated or overexpressed after SCI, which are activated after SCI, or due to the loss of neurons expressing XIAP after SCI.…”

Calpain signaling: from biology to therapeutic opportunities in neurodegenerative disorders

“…As a result, using calpain inhibitors appears to be a potential therapy option for acute SCI. In an adult dog SCI model, blocking calpain activity with a particular calpain inhibitor (PD150606) combined with methylprednisolone sodium succinate (MPSS) reduced neuronal death, enhanced the canine Basso, Beattie, and Bresnahan locomotor score, and improved neuroprotection ( 81 ). These experimental findings demonstrated significantly lower neuronal loss and microglial cell invasion.…”