Abstract
The broad variety of substances that inhibit the action of the ubiquitin-proteasome system (UPS)—known as proteasome inhibitors—have been used extensively in previous studies, and they are currently frequently proposed as a novel form of cancer treatment and as a protective factor in intracerebral hemorrhage treatment. The experimental data on the safest route of proteasome inhibitor administration, their associated side effects, and the possible ways of minimizing these effects have recently become a very important topic. The aim of our present study was to determine the effects of administering of MG-132, lactacystin and epoxomicin, compounds belonging to three different classes of proteasome inhibitors, on the ependymal walls of the lateral ventricle. Observations were made 2 and 8 weeks after the intraventricular administration of the studied substances dissolved in dimethyl sulfoxide (DMSO) into the lateral ventricle of adult Wistar rats. Qualitative and quantitative analysis of brain sections stained with histochemical and inmmunofluorescence techniques showed that the administration of proteasome inhibitors caused a partial occlusion of the injected ventricle in all of the studied animals. The occlusion was due to ependymal cells damage and subsequent ependymal discontinuity, which caused direct contact between the striatum and the lateral nuclei of the septum, mononuclear cell infiltration and the formation of a glial scar between these structures (with the activation of astroglia, microglia and oligodendroglia). Morphologically, the ubiquitin-positive aggregates corresponded to aggresomes, indicating impaired activity of the UPS and the accumulation and aggregation of ubiquitinated proteins that coincided with the occurrence of glial scars. The most significant changes were observed in the wall covering the striatum in animals that were administered epoxomicin, and milder changes were observed in animals administered lactacystin and MG-132. Interestingly, DMSO administration also caused damage to some of the ependymal cells, but the aggresome-like structures were not formed. Our results indicate that all of the studied classes of proteasome inhibitors are detrimental to ependymal cells to some extent, and may cause severe changes in the ventricular system. The safety implications of their usage in therapeutic strategies to attenuate intracerebral hemorrhagic injury and in brain cancer treatment will require further studies.
Highlights
The ubiquitin-proteasome system (UPS), the main system responsible for protein degradation in eukaryotic cells, has currently become the topic of very intensive research [1]
In all animals treated with proteasome inhibitors, a combination of these morphological changes led to glial scar formation, resulting in partial occlusion of the injected ventricle (Figs 1 and 2)
We showed that the degree of mononuclear cell infiltration is much more severe after the proteasome inhibitor treatment compared to that observed in the control group, and using the OX-42 antibody, we confirm that microglia are an important component of this infiltration
Summary
The ubiquitin-proteasome system (UPS), the main system responsible for protein degradation in eukaryotic cells, has currently become the topic of very intensive research [1]. The results of these studies helped to establish the relationships between UPS activity and neurodegenerative pathogenesis during aging, the inflammatory response, and the dynamics of tumour development [2, 3]. There is data from in vivo studies about the influence of proteasome inhibitors administered intraperitoneally [8, 9], subcutaneously [10], into the ventricular system [11] or after direct injection into selected brain structures [12,13,14] on cellular subpopulations in the nervous tissue. The aim of this study is to determine the changes that occur in the walls of the rat lateral ventricle after intraventricular administration of selected covalent proteasome inhibitors—MG-132 (an example of peptide aldehydes), lactacystin (an example of β-lactones and derivatives) and epoxomicin (an example of epoxyketones)
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