Serine proteases and brain damage – is there a link?

Gingrich, Melissa B.; Traynelis, Stephen F.

doi:10.1016/s0166-2236(00)01617-9

Cited by 254 publications

(191 citation statements)

References 82 publications

Supporting

Mentioning

189

Contrasting

Unclassified

Order By: Relevance

“…While still in an early stage, several possibilities based on previously acquired knowledge may direct the future research: First, given ANX2 is a potent co-activator of tPA/ plaminogen (Cesarman et al 1994;Kassam et al 1998), it is of great interest to investigate whether ANX2 is complexed with and required for neuronal tPA/plasminogen activation that has been shown to play an important role in synaptic plasticity and memory formation (Huang et al 1996;Frey et al 1996;Calabresi et al 2000;Baranes et al 1998;Pang et al 2004). Second, global activation of tPA/plasminogen can also be harmful to the brain and has been shown to trigger neuronal death (Gingrich and Traynelis 2000;Tsirka 2002;Siao and Tsirka 2002), which may involve in the activation of glial cells. Is ANX2 involved in this process?…”

Section: Discussionmentioning

confidence: 99%

Expression of annexin A2 in GABAergic interneurons in the normal rat brain

Zhao

2006

Journal of Neurochemistry

View full text Add to dashboard Cite

Expression of the Ca 2+ -dependent phospholipids binding protein annexin A2 (ANX2) in the brain is thought to be largely associated with brain pathological conditions such as tumor, inflammation, and neurodegeneration. The recent findings that ANX2 heterotetramer is involved in learning and neuronal activities necessitates a systematic investigation of the physiological expression of ANX2 in the brain. With combination of in situ hybridization and immunohistochemistry, ANX2 mRNA and protein were specifically detected in a group of GABAergic interneurons throughout the brain. Although ANX2 was absent from the interior of pyramidal neurons, it was found on the membrane and seemly the extracellular space of those neurons, where they closely co-localized with glutamate decarboxylase terminals. In cultured developing neurons, ANX2 was present at high concentrations in the growth cones co-distributing with several growth-associated proteins such as growth associated protein 43 (GAP43), turned on after division/Ulip/CRMP (TUC-4), tubulin, and tissue-plasminogen activator. It then became predominantly distributed on the membrane and mostly in axonal branches as neurons grew and extended synaptic networks. ANX2 was also secreted from cultured neurons, in a membrane-bound form that was Ca 2+ -dependent, which was significantly increased by neuronal depolarization. These results may have implications in the function and regulatory mechanism of ANX2 in the normal brain.

show abstract

Section: Discussionmentioning

confidence: 99%

Expression of annexin A2 in GABAergic interneurons in the normal rat brain

Zhao

2006

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…Some of the changes in this variable may be the consequence of BBB opening and the entry of not only water and the globular protein albumin, which has negligible MT effects, but also plasma-borne proteases (38), which then catalyze the breakdown of tissue proteins. Of the MT parameters studied, T 1sat was the most markedly affected by ischemia and reperfusion and T 1 the least (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Acute blood–brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging

Knight

Nagesh

Nagaraja³

et al. 2005

Magnetic Resonance in Med

View full text Add to dashboard Cite

Pathologic changes in brain tissue during and after stroke may lead to injury of the blood-brain barrier (BBB) and subsequent hemorrhagic transformation (HT). In a rat model of HT, the apparent diffusion coefficient of water, cerebral blood flow, relaxation times, T 1 and T 2 , and magnetization transfer (MT) related parameters (T 1sat , K for and the MT ratio) were repetitively measured during 3 h of focal ischemia and 2 h of reperfusion (n ‫؍‬ 8). Areas of BBB opening were identified by sequential assay of the transcapillary influx of Gd-diethylenetriaminepentaacetic acid (Gd-DTPA) by MRI and 14 C-␣-aminoisobutyric acid (AIB) by quantitative autoradiography. Ischemia-injured regions of interest were identified from the MRI data and divided into those with and without BBB opening. Of the several MRI parameters measured, the T 1sat in the caudate-putamen and preoptic area during ischemia and the first 2 h of reperfusion correlated best with the regional pattern of BBB opening observed thereafter. These data suggest that an ipsilateral/ contralateral T 1sat ratio > 1.6 demarcates leakage of small molecules such as Gd-DTPA and AIB across the BBB. Key words: Gd-DTPA; hemorrhagic transformation; magnetization transfer; MRI; rt-PA; stroke Thrombolysis using recombinant tissue plasminogen activator (rt-PA) has proven to be an effective intervention for the treatment of acute ischemic stroke (1), but the risk of hemorrhagic transformation (HT) following such treatment remains an obstacle to widespread usage of thrombolytic agents. To illustrate this risk, the probability of symptomatic HT increases significantly during the first 36 h after stroke onset in patients receiving rt-PA (6.4% vs. 0.6% in placebo-treated patients), and 61% of the patients with symptomatic HT die within 3 months (1). Studies performed using animal stroke models show similar findings with increased risk of HT associated with thrombolytics (2-5). In view of these complications with thrombolytic therapy, it is important to develop diagnostic imaging techniques that reliably identify tissue regions that are prone to HT and to obtain such data when deciding on a treatment protocol.One of the possible imaging techniques is computed tomography (CT). The sensitivity of CT for detection of early ischemic damage remains controversial because a significant proportion of stroke patients show negative acute CT images but go on to develop large infarcts (6). Although it is the standard diagnostic test for extant cerebral bleeding, CT has a limited capacity to predict HT in ischemic stroke (7). An early report from the NINDS rt-PA Stroke Trial showed only a 57% efficiency for the prediction of symptomatic HT based on early CT findings (1). A more recent retrospective analysis of CT films from the trial adjusted the data for group imbalances in several baseline clinical features and found that early ischemic changes were not predictive of clinical deterioration at 24 h or of symptomatic intracerebral hemorrhage (i.e., death) at 90 days (8). It may be that high...

show abstract

“…Thrombin (EC 3.4.21.5, factor IIa) is a serine protease catalyzing the cleavage of fibrinogen and the activation of several other components of the blood coagulation cascade (1)(2)(3). The proteolytically active Arg-specific enzyme of about 39 kDa derives from its 72-kDa zymogen (prothrombin, factor II) via cleavage by the factor Xa-containing prothrombinase complex, while certain inhibitors can serve in its inactivation.…”

mentioning

confidence: 99%

The Microglia-activating Potential of Thrombin

Hanisch

Rossum

Xie

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The serine protease thrombin is known as a blood coagulation factor. Through limited cleavage of proteinase-activated receptors it can also control growth and functions in various cell types, including neurons, astrocytes, and microglia (brain macrophages). A number of previous studies indicated that thrombin induces the release of proinflammatory cytokines and chemokines from microglial cells, suggesting another important role for the protease beyond hemostasis. In the present report, we provide evidence that this effect is not mediated by any proteolytic or non-proteolytic mechanism involving thrombin proper. Inhibition of the enzymatic thrombin activity did not affect the microglial release response. Instead the cyto-/chemokine-inducing activity solely resided in a high molecular weight protein fraction that could be isolated in trace amounts even from apparently homogenous ␣-and ␥-thrombin preparations. High molecular weight material contained thrombin-derived peptides as revealed by mass spectrometry but was devoid of thrombin-like enzymatic activity. Separated from the high molecular weight fraction by fast protein liquid chromatography, enzymatically intact ␣-and ␥-thrombin failed to trigger any release. Our findings may force a revision of the notion that thrombin itself is a direct proinflammatory release signal for microglia. In addition, they could be relevant for the study of other cellular activities and their assignment to this protease.

show abstract

Serine proteases and brain damage – is there a link?

Cited by 254 publications

References 82 publications

Expression of annexin A2 in GABAergic interneurons in the normal rat brain

Expression of annexin A2 in GABAergic interneurons in the normal rat brain

Acute blood–brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging

The Microglia-activating Potential of Thrombin

Contact Info

Product

Resources

About