Cystatin C Has a Dual Role in Post-Traumatic Brain Injury Recovery

Abstract

Cathepsin B is one of the major lysosomal cysteine proteases involved in neuronal protein catabolism. This cathepsin is released after traumatic injury and increases neuronal death; however, release of cystatin C, a cathepsin inhibitor, appears to be a self-protective brain response. Here we describe the effect of cystatin C intracerebroventricular administration in rats prior to inducing a traumatic brain injury. We observed that cystatin C injection caused a dual response in post-traumatic brain injury recovery: higher doses (350 fmoles) increased bleeding and mortality, whereas lower doses (3.5 to 35 fmoles) decreased bleeding, neuronal damage and mortality. We also analyzed the expression of cathepsin B and cystatin C in the brains of control rats and of rats after a traumatic brain injury. Cathepsin B was detected in the brain stem, cerebellum, hippocampus and cerebral cortex of control rats. Cystatin C was localized to the choroid plexus, brain stem and cerebellum of control rats. Twenty-four hours after traumatic brain injury, we observed changes in both the expression and localization of both proteins in the cerebral cortex, hippocampus and brain stem. An early increase and intralysosomal expression of cystatin C after brain injury was associated with reduced neuronal damage.

Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate

“…By contrast, only a few glia cells in normal brain were seen to contain significant amounts of cathepsin B ( 168 ). A similar intense neuronal cell staining was also seen in rodent brain, especially in the pyramidal cells of the cortex, large neurocytes of the septal region, many hippocampal neurons, and magnocellular nerve cells of the hypothalamus ( 97 , 168 , 172 , 173 ).…”

“…Our data in a severe CCI mouse model show a 100% and 380% increase in brain cathepsin B activity and protein levels at 2 and 24 h post-trauma, respectively ( 48 ). Trauma elevates cathepsin B protein levels 1 day to 3 days post injury in a moderate closed-skull TBI rat model and this increase varied with injury location ( 97 ). The prolonged elevation of cathepsin B after trauma suggests that it may be possible to therapeutically intervene clinically, as treatment often does not begin until several hours after injury.…”

“…The high cystatin C to cathepsin B ratios show that inhibiting cathepsin B activity in these compartments is critical, especially in the brain. TBI increases cystatin C and an increase in cystatin C soon after trauma is associated with reduced neuronal cell damage ( 97 ).…”

Diurnal Variation Induces Neurobehavioral and Neuropathological Differences in a Rat Model of Traumatic Brain Injury

“…Although this scale was primarily designed to evaluate cerebral ischemia, cerebral ischemia and trauma share similar pathophysiological mechanisms ( Leker and Shohami, 2002 ). In fact, we have previously used this scale to assess neurological damage after TBI ( Martinez-Vargas et al, 2012 , 2014 ; Estrada-Rojo et al, 2018 ).…”

Serum cystatin C is increased in acute spinal cord injury: a multicentre retrospective study

“…A high level of this biomarker has been observed in the cerebrospinal fluid (CSF) of people who have had a traumatic brain injury, including both children and adults. In addition, many animal experiments have shown that CysC protects the brain from secondary injury by various mechanisms [5,6]. Furthermore, a study of acute cerebral stroke found that CysC was an independent predictor of infarct size and haemorrhage volume [7].…”