The Importance of Thrombin in Cerebral Injury and Disease

Abstract

There is increasing evidence that prothrombin and its active derivative thrombin are expressed locally in the central nervous system. So far, little is known about the physiological and pathophysiological functions exerted by thrombin in the human brain. Extra-hepatic prothrombin expression has been identified in neuronal cells and astrocytes via mRNA measurement. The actual amount of brain derived prothrombin is expected to be 1% or less compared to that in the liver. The role in brain injury depends upon its concentration, as higher amounts cause neuroinflammation and apoptosis, while lower concentrations might even be cytoprotective. Its involvement in numerous diseases like Alzheimer's, multiple sclerosis, cerebral ischemia and haemorrhage is becoming increasingly clear. This review focuses on elucidation of the cerebral thrombin expression, local generation and its role in injury and disease of the central nervous system.

Keywords: Alzheimer’s disease; Parkinson’s disease; cerebral thrombin system; intracerebral haemorrhage; multiple sclerosis; prothrombin; stroke; thrombin.

Figure 1

Parkinson’s disease. In PD a progressive loss of dopaminergic neurons and microglia activation in the substantia nigra pars compact (SNpc), is characteristic. Microglia activation by thrombin leads to the expression of NO, IL-1β, IL-6 and TNF-α, which causes a release of caspase-3 and p53 from the dopaminergic neurons and results in neuronal death. On the other hand, PAR-1 activation in astrocytes seems to exert a more neuroprotective influence.

Figure 2

Alzheimer’s disease. In brains of patients with AD, thrombin is present in senile plaques, amyloid deposits, microvessels and neurofibrillary tangles. Thrombin-dependent activation of PAR1/4 results in hyperphosphorylation and aggregation of tau protein leading to apoptosis of predominantly hippocampal neurons. Furthermore, thrombin induces the cleavage of amyloid-β precursor protein (β-APP) leading to the amyloid β (Aβ) accumulation (amyloid plaques), which have neurotoxic capacity. Additionally, microglia activation by thrombin leads to the generation of reactive oxygen species (ROS) and proinflammatory proteins e.g., IL-8.

Figure 3

Multiple sclerosis. In MS fibrin deposits are related to axonal damage and demyelination. Thrombin-dependent PAR-1 activation on oligodendrocytes mediates the release of proinflammatory factors such as TNF-α or matrix metalloproteinase-9 (MMP-9). Furthermore, increased thrombin activity in the spinal cord was associated with increased microglia activation and neuronal demyelination, which correlate with a disease progression and neurological deficits.

Figure 4

Stroke/intracerebral haemorrhage. Ischemia of brain-tissue leads to an increase in local thrombin and to thrombin influx via BBB breakdown. Thrombin concentrations in pico- to nanomolar range (10 pM–10 nM) are shown to protect hippocampal neurons and astrocytes from a variety of cellular insults. In sharp contrast, for higher concentrations in nano- to micromolar range (10 nM–10 μM) adverse effects, such as increased death of motor neurons and cells of the hippocampus, are documented. Oedema formation after ICH is linked with BBB breakdown and increased thrombin infusion leading to TNF-α and MMP-9 up-regulation. The release of proinflammatory factors contributes to neuroinflammation and neurodegeneration.

Figure 5

2D chemical structure of common direct acting thrombin inhibitors (DIT). The given structures depict the low molecular weight DTIs: the prodrug dabigatran etexilate, the active principle dabigatran and argatroban [158,159].