Ethamsylate Attenuates Mutilated Secondary Pathogenesis and Exhibits a Neuroprotective Role in Experimental Model of Spinal Cord Injury.

Deficits in the neuronal connection that succumbs to the impairment of sensory and motor neurons are the hallmarks of spinal cord injury (SCI). Secondary pathogenesis, which initiates after the primary mechanical insult to the spinal cord, depicts a pivotal role in producing inflammation, lesion formation and ultimately causes fibrotic scar formation in the chronic period. This fibrotic scar formed acts as a major hindrance in facilitating axonal regeneration and is one of the root causes of motor impairment. Cascade of secondary events in SCI begins with injury-induced blood spinal cord barrier rupture that promotes increased migration of neutrophils, macrophages, and other inflammatory cells at the injury site to initiate the secondary damages. This phenomenon leads to the release of matrix metalloproteinase, cytokines and chemokines, reactive oxygen species, and other proteolytic enzymes at the lesion site. These factors assist in the activation of the TGF-ß1 signaling pathway, which further leads to excessive proliferation of perivascular fibroblast, followed by deposition of collagen and fibronectin matrix, which are the main components of the fibrotic scar. Subsequently, this scar formed inhibits the propagation of action potential from one neuron to adjacent neurons. Ethamsylate, an anti-hemorrhagic drug, has the potential to maintain early hemostasis as well as restore capillary resistance. Therefore, we hypothesized that ethamsylate, by virtue of its anti-hemorrhagic activity, reduces hemorrhagic ischemia-induced neuronal apoptosis, maintains the blood spinal cord barrier integrity, and decreases secondary damage severity, thereby reduce the extent of fibrotic scar formation, and demonstrates a neuroprotective role in SCI.

Tomographic Imaging and Correlation to Quantify Vascular and Inflammatory Changes in an Experimental Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating condition causing the loss of sensory and motor functions. SCI pathology is multifaceted, encompassing inflammation, scarring, neuronal damage, and vascular and tissue remodeling. The dynamics of SCI rapidly transform from acute, sub-acute, and chronic phases. The rapidly changing environment necessitates the real-time monitoring of disease severity. Therefore, in this study, we used the IVIS spectrum, a noninvasive fluorescence imaging modality, to monitor the disease pathology in live animals. We used near-infrared fluorescence imaging agents including Angiosense 750 EX, a probe that detects vascular changes, and Cat B 680 FAST, a probe that detects inflammation at various day points post injury (DPI), that is, DPI-1, DPI-14, and DPI-28. We quantified the pathophysiological changes after SCI using IVIS in live animals. As a result, we observed distinct differences in the disease progression between injured and sham mice. Moreover, live imaging showed a good correlation with behavioral studies, protein expression, and immunohistological analysis. Hence, the goal of this study was to introduce a new optical imaging modality that offers a determination of disease severity and the advantage of accelerated imaging of the correlated biomarkers in a real-time and dynamic manner. This study concluded that Cat B 680 Fast and Angiosense 750 EX could be used to assess the disease severity after SCI. Furthermore, our study suggests that the noninvasive fluorescence optical imaging modality offers a unique approach in monitoring neuroinflammatory diseases in live animals.