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Open Access Research

Dipeptidyl peptidase IV, aminopeptidase N and DPIV/APN-like proteases in cerebral ischemia

Peter Röhnert12, Werner Schmidt13, Patrick Emmerlich1, Alexander Goihl4, Sabine Wrenger4, Ute Bank5, Karsten Nordhoff15, Michael Täger5, Siegfried Ansorge5, Dirk Reinhold4 and Frank Striggow13*

Author Affiliations

1 KeyNeurotek Pharmaceuticals AG, Leipziger Str. 44, D-39120 Magdeburg, Germany

2 European Screeningport GmbH, Schnackenburgallee 114, D-22525 Hamburg, Germany

3 Department of Neurodegeneration and Intervention Strategies, German Center for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, D-39120 Magdeburg, Germany

4 Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University, Medical Faculty, Leipziger Str. 44, D-39120 Magdeburg, Germany

5 IMTM GmbH, Leipziger Str. 44, D-39120 Magdeburg, Germany

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Journal of Neuroinflammation 2012, 9:44  doi:10.1186/1742-2094-9-44

Published: 28 February 2012

Abstract

Background

Cerebral inflammation is a hallmark of neuronal degeneration. Dipeptidyl peptidase IV, aminopeptidase N as well as the dipeptidyl peptidases II, 8 and 9 and cytosolic alanyl-aminopeptidase are involved in the regulation of autoimmunity and inflammation. We studied the expression, localisation and activity patterns of these proteases after endothelin-induced occlusion of the middle cerebral artery in rats, a model of transient and unilateral cerebral ischemia.

Methods

Male Sprague-Dawley rats were used. RT-PCR, immunohistochemistry and protease activity assays were performed at different time points, lasting from 2 h to 7 days after cerebral ischemia. The effect of protease inhibitors on ischemia-dependent infarct volumes was quantified 7 days post middle cerebral artery occlusion. Statistical analysis was conducted using the t-test.

Results

Qualitative RT-PCR revealed these proteases in ipsilateral and contralateral cortices. Dipeptidyl peptidase II and aminopeptidase N were up-regulated ipsilaterally from 6 h to 7 days post ischemia, whereas dipeptidyl peptidase 9 and cytosolic alanyl-aminopeptidase were transiently down-regulated at day 3. Dipeptidyl peptidase 8 and aminopeptidase N immunoreactivities were detected in cortical neurons of the contralateral hemisphere. At the same time point, dipeptidyl peptidase IV, 8 and aminopeptidase N were identified in activated microglia and macrophages in the ipsilateral cortex. Seven days post artery occlusion, dipeptidyl peptidase IV immunoreactivity was found in the perikarya of surviving cortical neurons of the ipsilateral hemisphere, whereas their nuclei were dipeptidyl peptidase 8- and amino peptidase N-positive. At the same time point, dipeptidyl peptidase IV, 8 and aminopeptidase N were targeted in astroglial cells. Total dipeptidyl peptidase IV, 8 and 9 activities remained constant in both hemispheres until day 3 post experimental ischemia, but were increased (+165%) in the ipsilateral cortex at day 7. In parallel, aminopeptidase N and cytosolic alanyl-aminopeptidase activities remained unchanged.

Conclusions

Distinct expression, localization and activity patterns of proline- and alanine-specific proteases indicate their involvement in ischemia-triggered inflammation and neurodegeneration. Consistently, IPC1755, a non-selective protease inhibitor, revealed a significant reduction of cortical lesions after transient cerebral ischemia and may suggest dipeptidyl peptidase IV, aminopeptidase N and proteases with similar substrate specificity as potentially therapy-relevant targets.

Keywords:
Cerebral schemia; Stroke; Middle cerebral artery occlusion; DPIV; Aminopeptidase N