Trends in Neurosciences
Volume 23, Issue 9, 1 September 2000, Pages 399-407
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Serine proteases and brain damage – is there a link?

https://doi.org/10.1016/S0166-2236(00)01617-9Get rights and content

Abstract

The protective blood–brain barrier normally allows diffusion of small molecules such as oxygen and carbon dioxide, and transport of essential nutrients, but excludes large proteins and other blood constituents from the interstitial space of the CNS. However, head trauma, stroke, status epilepticus and other pathological conditions can all compromise the integrity of this barrier, and allow blood proteins as large as albumin to gain access to the extracellular spaces that surround neurons and glia. Given their possible entry into brain tissue during cerebrovascular insult, the effects of blood-derived proteases such as thrombin, tissue plasminogen activator and plasmin in the CNS have come under increasing scrutiny. Evidence now supports a role for serine proteases in the sequence of events that can lead to glial scarring, edema, seizure and neuronal death.

Section snippets

Protease-activated receptors

Thrombin is a serine protease that is generated by proteolysis of its precursor (prothrombin) at sites of vascular injury. Thrombin stimulation of platelets and limited proteolysis of fibrinogen enable clot formation and wound healing in blood vessels. Many of the actions of thrombin can be traced to PARs. To date, cDNAs encoding four PAR receptors (PAR1–4) have been identified1, 2, 3, 4, 5 and three of these genes (human PAR1, PAR2, PAR3) map to a single chromosome (5q13) in a gene cluster6;

Localization of protease receptors and inhibitors in the brain

The first thrombin receptor to be cloned, PAR1, is widely distributed in neurons and glia23, 24. PAR1 mRNA is widespread in prenatal rat brain tissue, and becomes more pronounced and confined to particular cell types in adult animals23, 24. This developmental profile differs from that of prothrombin mRNA, which is transiently reduced near birth25, raising the possibility that serine proteases and their receptors might play different roles in pre-, neo- and postnatal brain. Hybridization of PAR1

Entry of serine proteases into brain tissue

BBB breakdown associated with cerebrovascular insult reflects a largely nonselective increase in the permeability of brain capillaries and tight junctions to high-molecular-weight proteins (Box 2). Although serine protease extravasation into brain tissue during pathological situations is undocumented, the potential entry of serine proteases into the brain deserves careful consideration in the following three scenarios.

(1) Thrombin will enter interstitial fluid during penetrating head wound,

Pathological effects of serine proteases on neurons and glial cells

The molecular and cellular processes that lead to neuronal death following brain trauma and cerebrovascular insult are diverse and currently under intense investigation. Serine proteases trigger a variety of effects in neurons and glia that are often associated with brain damage (Fig. 3).

Outlook

An increasing body of literature describing the effects of serine proteases on glial and neuronal function suggests that understanding protease signaling in the brain could improve understanding of the neuropathology associated with BBB breakdown. The next few years will be pivotal in determining if serine protease extravasation, aberrant PAR activation, or cleavage of non-PAR substrates contribute to brain damage and thus are potential therapeutic targets. The many mechanisms by which serine

Acknowledgements

The author’s thank D. Cunningham, R. Dingledine, J.T. Greenamyre and S. Strickland for critical comments on the manuscript and the NIMH (MBG), NINDS (SFT) and John Merck Fund (SFT), whose generous support made this work possible.

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