Can two enzymes work together to worsen brain-cell damage after a brain hemorrhage?

Details

Rapid loss of neurons is a major pathological outcome of intracerebral hemorrhage (ICH). Several mechanisms may contribute to this neurotoxicity, including protein-cutting enzymes such as thrombin and matrix metalloproteinase-9 (MMP-9).

This experimental study tested whether thrombin and MMP-9 combine to injure cultured neurons and interact to promote acute neurotoxicity in ICH in vivo. In cultures of human fetal neurons, exposure to either thrombin or MMP-9 alone caused neuronal death, and combining the two enzymes increased neurotoxicity. Thrombin toxicity involved protease-activated receptor-1 and the conversion of proMMP-9 into active MMP-9.

For the animal experiments, the researchers induced ICH in mice by injecting the animals' own blood into the brain. By 24 hours after injury, substantial areas of brain damage, neuronal death, microglia/macrophage activation, and neutrophil accumulation had occurred. These neuropathological features were reduced in MMP-9-null mice compared with wild-type controls. Concurrently blocking thrombin with hirudin also alleviated injury in the MMP-9-null mice.

The researchers concluded that thrombin and MMP-9 collaborate to promote neuronal death in culture and in ICH. They argued that improving the prognosis of ICH requires early, simultaneous inhibition of the neurotoxic actions of both enzymes after injury.