ABSTRACT
Transglutiminase-2 (TG2) is a multifunctional enzyme that has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) using global knockout mice and TG2 selective inhibitors. Previous studies have identified the expression of TG2 in subsets of macrophages-microglia and astrocytes after EAE. The aims of the current investigation were to examine neuronal expression of TG2 in rodent models of chronic-relapsing and non-relapsing EAE and through co-staining with intracellular and cell death markers, provide insight into the putative role of TG2 in neuronal pathology during disease progression. Here we report that under normal physiological conditions there is a low basal expression of TG2 in the nucleus of neurons, however following EAE or MS, robust induction of cytoplasmic TG2 occurs in most neurons surrounding perivascular lesion sites. Importantly, TG2-positive neurons also labeled for phosphorylated Extracellular signal-regulated kinase 1/2 (ERK1/2) and the apoptotic marker cleaved caspase-3. In white and gray matter lesions, high levels of TG2 were also found within the vasculature and endothelial cells as well as in tissue migrating pericytes or fibroblasts, though rarely did TG2 colocalize with cells identified with glial cell markers (astrocytes, oligodendrocytes and microglia). TG2 induction occurred concurrently with the upregulation of the blood vessel permeability factor and angiogenic molecule Vascular Endothelial Growth Factor (VEGF). Extracellular TG2 was found to juxtapose with fibronectin, within and surrounding blood vessels. Though molecular and pharmacological studies have implicated TG2 in the induction and severity of EAE, the cell autonomous functions of this multifunctional enzyme during disease progression remains to be elucidated.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , GTP-Binding Proteins/genetics , Multiple Sclerosis , Transglutaminases/genetics , Animals , Endothelial Cells , Mice , Mice, Knockout , Neurons , Protein Glutamine gamma Glutamyltransferase 2 , Vascular Endothelial Growth Factor AABSTRACT
The so-called "club drug" Foxy or Methoxy Foxy (5-Methoxy-N,N-di(iso)propyltryptamine hydrochloride; 5-MeO-DIPT) is a newer drug of abuse that has recently gained in popularity among recreational users as an alternative to MDMA (Ecstasy). While considerable research into the consequences of MDMA use is available, much remains unknown about the neurobiological consequences of 5-MeO-DIPT use. In the present study, beginning at 35 days of age adolescent rats were given repeated injections of 10 mg/kg of 5-MeO-DIPT, MDMA, or a corresponding volume of isotonic saline. Adult animals (135 days old) were trained and tested on a number of tasks designed to assess the impact, if any, and severity of 5-MeO-DIPT and MDMA, on a series of spatial and nonspatial memory tasks. Both the 5-MeO-DIPT- and the MDMA-treated rats were able to master the spatial navigation tests where the task included a single goal location and all groups performed comparably on these phases of training and testing. Conversely, the performance of both groups of the drug-treated rats was markedly inferior to that of the control animals on a task where the goal was moved to a new location and on a response learning task, suggesting a lack of flexibility in adapting their responses to changing task demands. In addition, in a response learning version of a learning set task, 5-MeO-DIPT rats made significantly more working memory errors than MDMA or control rats. Results are discussed in terms of observed alterations in serotonin activity in the forebrain and the consequences of compromised serotoninergic systems on cognitive processes.(AU)
Subject(s)
Animals , Rats , N-Methyl-3,4-methylenedioxyamphetamine/adverse effects , Illicit Drugs/adverse effects , Neurocognitive Disorders/chemically inducedABSTRACT
The so-called "club drug" Foxy or Methoxy Foxy (5-Methoxy-N,N-di(iso)propyltryptamine hydrochloride; 5-MeO-DIPT) is a newer drug of abuse that has recently gained in popularity among recreational users as an alternative to MDMA (Ecstasy). While considerable research into the consequences of MDMA use is available, much remains unknown about the neurobiological consequences of 5-MeO-DIPT use. In the present study, beginning at 35 days of age adolescent rats were given repeated injections of 10 mg/kg of 5-MeO-DIPT, MDMA, or a corresponding volume of isotonic saline. Adult animals (135 days old) were trained and tested on a number of tasks designed to assess the impact, if any, and severity of 5-MeO-DIPT and MDMA, on a series of spatial and nonspatial memory tasks. Both the 5-MeO-DIPT- and the MDMA-treated rats were able to master the spatial navigation tests where the task included a single goal location and all groups performed comparably on these phases of training and testing. Conversely, the performance of both groups of the drug-treated rats was markedly inferior to that of the control animals on a task where the goal was moved to a new location and on a response learning task, suggesting a lack of flexibility in adapting their responses to changing task demands. In addition, in a response learning version of a learning set task, 5-MeO-DIPT rats made significantly more working memory errors than MDMA or control rats. Results are discussed in terms of observed alterations in serotonin activity in the forebrain and the consequences of compromised serotoninergic systems on cognitive processes.
