Neuroprotektion und Regeneration nach Durchtrennung des Sehnervs

P. Heiduschka; D. Fischer; S. Thanos

doi:10.1055/s-2004-813054

Klinische Monatsblätter für Augenheilkunde, Table of Contents

Klin Monbl Augenheilkd 2004; 221(8): 684-701
DOI: 10.1055/s-2004-813054

Übersicht

Neuroprotektion und Regeneration nach Durchtrennung des Sehnervs

Neuroprotection and Regeneration after Traumatic Lesion of the Optic NerveP. Heiduschka¹ , D. Fischer² , S. Thanos³

¹Novartis Pharma AG, NIBR, WKL-126.3.05, Klybeckstr., Porte 15, CH-4002 Basel, Schweiz
²Children’s Hospital, Harvard Medical School, 314 Enders Building, 300 Longwood Ave., Boston (MA) 02115, USA
³Universitätsaugenklinik Münster, Abteilung für Experimentelle Ophthalmologie, Domagkstraße 15, 48149 Münster

Die hier vorgestellten Arbeiten wurden unterstützt durch das Ministerium für Bildung und Forschung (Nr. 01 Ko 9805/7, Nr. 01 KS 9604/0) und das Interdisziplinäre Zentrum für Klinische Forschung Münster (3. Förderperiode, IZKF Projekt Nr. F7).

Abstract

Zusammenfassung

Hintergrund: Nach einer traumatischen Läsion des Sehnervs kommt es zu einer progressiven Degeneration von retinalen Ganglienzellen (RGZ) durch Apoptose und damit einem Verlust der Sehfähigkeit des betroffenen Auges. Wie auch andere Neurone des zentralen Nervensystems können die RGZ ihre geschädigten Axone nicht spontan regenerieren. Wir setzten spezielle chirurgische und pharmakologische Methoden ein, um das Überleben der RGZ und die Regeneration ihrer Axone zu erreichen. Material und Methoden: Die Untersuchungen fanden am Modell der Degeneration der RGZ nach einer Schädigung des Sehnervs der adulten Ratte statt. Die RGZ wurden mit einem Fluoreszenzfarbstoff beladen und verschiedene Substanzen wurden intravitreal appliziert. Nach zwei Wochen wurden die Effekte anhand der Anzahl der überlebenden RGZ quantifiziert. Für die Untersuchungen zur Regeneration wurde an den Stumpf des Sehnervs ein autologes peripheres Transplantat angenäht oder die beiden Enden des durchtrennten Sehnervs wurden wieder zusammengenäht. Die Wiederherstellung der Funktion der RGZ wurde mittels VEP-Messungen untersucht. Ergebnisse: Die Anzahl der eine Axotomie überlebenden RGZ stieg signifikant nach intravitrealen Injektionen von Aurintricarboxylsäure, Cortisol, eines Caspase-Hemmers, Brimonidin oder Mikroglia-gerichteter Substanzen an. Die Regeneration der durchtrennten Axone konnte durch Aurintricarboxylsäure oder Cortisol verstärkt werden. Erhebliche neuroprotektive und regenerative Effekte einschließlich einer partiellen Wiederherstellung des VEP konnten durch die Induktion einer Linsenverletzung, welche zu einer allmählichen Freisetzung von Kristallinen in den Glaskörper führt, oder durch die intravitreale Injektion von aufgereinigten Kristallinen erreicht werden. Schlussfolgerung: Durch geeignete neuroprotektive Maßnahmen kann der bislang unvermeidliche Verlust der Sehfähigkeit nach einem Sehnervtrauma im Tiermodell verhindert werden, was die Entwicklung von Behandlungsmethoden für Patienten hoffnungsvoll erscheinen lässt.

Abstract

Background: After a traumatic lesion of the optic nerve, retinal ganglion cells (RGC) undergo massive degeneration by apoptosis, which leads to loss of vision in the affected eye. Like other neurones in the central nervous system, RGC are not able to regenerate their damaged axons spontaneously. We used special surgical methods and pharmacological measures to achieve enhanced survival and regeneration of damaged RGC. Materials and Methods: Studies were performed using the model of RGC degeneration induced by severing the optic nerve of adult rats. RGC were loaded with a fluorescent dye, and several drugs were applied intravitreally. The effects were evaluated after two weeks by counting the surviving RGC. For regeneration studies, an autologous peripheral nerve graft was sutured to the stump of the cut optic nerve, or the ends of the cut optic nerve were re-sutured. Recovery of RGC function was assessed by VEP measurements. Results: The number of RGC surviving an axotomy increased significantly after intravitreal injections of aurintricarboxylic acid, cortisol, a caspase inhibitor, brimonidine or microglia-targeted substances. Regeneration of cut axons was enhanced by aurintricarboxylic acid or cortisol. In addition, considerable neuroprotective and regenerative effects including partial restoration of VEP were induced by lens injury, which results in a gradual release of crystallins into the vitreous, or by intravitreal injection of purified crystallins. Conclusion: The loss of vision after an optic nerve trauma can be reduced in this animal model by suitable neuroprotective measures, which raises hope for the treatment of patients.

Schlüsselwörter

Retinale Ganglienzellen - Trauma - Sehnerv - Apoptose - Neuroprotektion - Regeneration - Aurintricarboxylsäure - Linsenverletzung - Kristallin - VEP

Key words

Retinal ganglion cells - trauma - optic nerve - apoptosis - neuroprotection - regeneration - aurintricarboxylic acid - lens injury - crystallin - VEP

Full Text

References

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