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1.
Dialogues Clin Neurosci ; 13(3): 279-86, 2011.
Article in English | MEDLINE | ID: mdl-22034462

ABSTRACT

Traumatic brain injury remains a major cause of death and disability; it is estimated that annually 10 million people are affected. Preclinical studies have shown the potential therapeutic value of stem cell therapies. Neuroprotective as well as regenerative properties of stem cells have been suggested to be the mechanism of action in preclinical studies. However, up to now stem cell therapy has not been studied extensively in clinical trials. This article summarizes the current experimental evidence and points out hurdles for clinical application. Focusing on a cell therapy in the acute stage of head injury, the potential of encapsulated cell biodelivery as a novel cell-therapeutic approach will also be discussed.


Subject(s)
Brain Injuries/therapy , Cell- and Tissue-Based Therapy/methods , Glucagon-Like Peptide 1/administration & dosage , Mesenchymal Stem Cell Transplantation/methods , Translational Research, Biomedical , Animals , Humans , Transfection/methods
2.
Neurosci Lett ; 497(1): 6-10, 2011 Jun 15.
Article in English | MEDLINE | ID: mdl-21507341

ABSTRACT

Encapsulated human mesenchymal stem cells(MSC) are studied in a double transgenic mouse model of Alzheimer's disease (AD) after intraventricular implantation at 3 months of age. Abeta 40/42 deposition, and glial (GFAP) and microglial (CD11b) immunoreactivity were investigated 2 months after transplantation of either native MSC or MSC transfected with glucagon-like peptide-1 (GLP-1). CD11b immunostaining in the frontal lobes was significantly decreased in the GLP-1 MSC group compared to the untreated controls. Also, the plaque associated GFAP immunoreactivity was only observed in one of four animals in the GLP-1 MSC group. Abeta 40 whole brain ELISA was decreased in the MSC group: 86.06±5.2 pg/ml (untreated control) vs. 78.67±11.2 pg/ml (GLP-1 MSC group) vs.70.9±11.1 pg/ml (MSC group, p<0.05). Intraventricular transplantation of native and GLP-1 transfected MSC has been shown effective. Decreased amyloid deposition or suppression of glial and microglial responses were observed. However, encapsulation of MSC may alter their biological activity.


Subject(s)
Alzheimer Disease/therapy , Genetic Therapy/methods , Glucagon-Like Peptide 1/genetics , Mesenchymal Stem Cell Transplantation/methods , Alginates/pharmacology , Amyloid beta-Peptides/analysis , Amyloid beta-Peptides/metabolism , Animals , Biocompatible Materials/pharmacology , Capsules , Cell Line , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Glucuronic Acid/pharmacology , Hexuronic Acids/pharmacology , Humans , Male , Mesenchymal Stem Cells , Mice , Mice, Transgenic , Transfection
3.
Brain Res ; 1317: 286-96, 2010 Mar 04.
Article in English | MEDLINE | ID: mdl-20045398

ABSTRACT

AD pathology is often seen in cortical biopsies of NPH patients. It remains unclear whether these findings are coincidental or causally related. In an aged animal model of NPH, we quantify Abeta and pTau accumulation and describe its temporal and spatial distribution. One-year-old male Sprague-Dawley rats had hydrocephalus induced by cisternal kaolin injection. Immunohistochemistry (IMHC) for AbetaPP, Abeta40, Abeta42 and pTau (epitope pT231) and ELISA for Abeta40, Abeta42 and pT231 were performed on controls and after 2, 6 and 10 weeks of hydrocephalus. Rats had double-label fluorescence IMHC for localization of Abeta42 and pT231. IMHC showed no change in neuronal AbetaPP expression following hydrocephalus. Abeta42 appeared earliest in CSF clearance pathways, p<0.05, and also showed significant rises in perivascular spaces and in cortical parenchyma. Mean ELISA values for Abeta40 and Abeta42 increased three- to four-fold in hydrocephalic rats at 6 and 10 weeks. Abeta40 increased between 2 and 6 weeks (p=0.0001), and remained stable at 10 (p=0.0002); whereas Abeta42 was elevated at 2 weeks (p<0.04) and remained at 6 (p=0.015). PTau at 6 and 10 weeks showed AD-like increased neuronal somatic staining and loss of dendritic staining. ELISA demonstrated increased pT231 in hydrocephalic rats at 10 weeks (p<0.0002). Double-label fluorescence for Abeta42 and pT231 revealed intraneuronal co-localization. Hydrocephalus in the elderly rat, therefore, can induce both Abeta and pTau accumulation. As distinct from brain injury models, no increase in AbetaPP expression was demonstrated. Rather, altered CSF dynamics appears to impair Abeta clearance in this NPH model.


Subject(s)
Aging/metabolism , Amyloid beta-Peptides/metabolism , Brain/metabolism , Hydrocephalus, Normal Pressure/metabolism , tau Proteins/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Cerebral Cortex/metabolism , Disease Models, Animal , Hippocampus/metabolism , Hydrocephalus, Normal Pressure/chemically induced , Kaolin , Male , Neurons/metabolism , Peptide Fragments/metabolism , Phosphorylation , Rats , Rats, Sprague-Dawley , Time Factors
4.
Neurosci Lett ; 463(3): 176-81, 2009 Oct 09.
Article in English | MEDLINE | ID: mdl-19638295

ABSTRACT

PURPOSE: "Naked" human mesenchymal stem cells (MSC) are neuro-protective in experimental brain injury (TBI). In a controlled cortical impact (CCI) rat model, we investigated whether encapsulated MSC (eMSC) act similarly, and whether efficacy is augmented using cells transfected to produce the neuro-protective substance glucagon-like peptide-1 (GLP-1). METHODS: Thirty two Sprague-Dawley rats were randomized to five groups: controls (no CCI), CCI-only, CCI+eMSC, CCI+GLP-1 eMSC, and CCI+empty capsules. On day 14, cisternal cerebro-spinal fluid (CSF) was sampled for measurement of GLP-1 concentration. Brains were immuno-histochemically assessed using specific antibody staining for NeuN, MAP-2 and GFAP. In another nine healthy rats, in vitro. RESULTS: GLP-1 production rates were measured from cells explanted after 2, 7 and 14 days. GLP-1 production rate in transfected cells, before implantation, was 7.03 fmol/capsule/h. Cells were still secreting GLP-1 at a rate of 3.68+/-0.49, 2.85+/-0.45 and 3.53+/-0.55 after 2, 7 and 14 days, respectively. In both of the stem cell treated CCI groups, hippocampal cell loss was reduced, along with an attenuation of cortical neuronal and glial abnormalities, as measured by MAP-2 and GFAP expression. The effects were more pronounced in animals treated with GLP-1 secreting eMSC. This group displayed an increased CSF level of GLP-1 (17.3+/-3.4pM). CONCLUSIONS: Hippocampal neuronal cell loss, and cortical glial and neuronal cyto-skeletal abnormalities, after CCI are reduced following transplantation of encapsulated eMSC. These effects were augmented by GLP-1 transfected eMSC.


Subject(s)
Brain Injuries/therapy , Cerebral Cortex/pathology , Mesenchymal Stem Cell Transplantation , Animals , Brain Injuries/metabolism , Brain Injuries/pathology , Capsules , Cerebral Cortex/metabolism , Cerebral Ventricles , Glucagon-Like Peptide 1/genetics , Glucagon-Like Peptide 1/metabolism , Male , Mesenchymal Stem Cells/metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Transfection
5.
Epilepsia ; 47(11): 1803-9, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17116018

ABSTRACT

PURPOSE: The current treatment of epilepsy focuses exclusively on the prophylaxis or suppression of seizures and thus provides merely a symptomatic treatment, without clear influence on the course of the disease. There is a need for new drugs that act at different molecular targets than currently available antiepileptic drugs (AEDs) and for new therapies designed to block the process of epileptogenesis. In recent years, different research lines have examined the epileptogenic process in order to understand the different stages in this process, and with the hope that early recognition and intervention could prevent the development or progression of epilepsy. In animals, acquired epilepsy is studied most commonly with the kindling model and status epilepticus models. In the present study, we used the kindling model to evaluate whether the novel AED lacosamide affects kindling-induced epileptogenesis. This drug does not seem to act by any of the mechanisms of currently available AEDs, but the exact molecular mechanisms of action of lacosamide have not yet been clarified. METHODS: Groups of 9-10 rats were treated with either vehicle or different doses of lacosamide (3, 10, or 30 mg/kg/day) over 22-23 days during amygdala kindling. RESULTS: Daily administration of lacosamide during kindling acquisition produced a dose-dependent effect on kindling development. While the drug was inactive at 3 mg/kg/day, significant retardation of kindling was observed at 10 mg/kg/day, by which the average number of stimulations to reach kindling criterion was increased by >90%. A significant inhibitory effect on kindling acquisition was also observed with 30 mg/kg/day, but this dose of lacosamide was associated with adverse effects. CONCLUSIONS: The present data demonstrate that lacosamide, in addition to exerting anticonvulsant activity, has the potential to retard kindling-induced epileptogenesis. Whether this indicates that lacosamide possesses antiepileptogenic or disease-modifying potential needs to be further evaluated, including studies in other models of acquired epilepsy.


Subject(s)
Acetamides/pharmacology , Amygdala/drug effects , Anticonvulsants/pharmacology , Epilepsy/prevention & control , Kindling, Neurologic/drug effects , Amygdala/physiopathology , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Electric Stimulation , Electrodes, Implanted , Electroencephalography/drug effects , Electroencephalography/statistics & numerical data , Epilepsy/physiopathology , Female , Kindling, Neurologic/physiology , Lacosamide , Rats , Rats, Wistar
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