Mesenchymal Stem Cells in a Transgenic Mouse Model of Multiple System Atrophy: Immunomodulation and Neuroprotection

Mesenchymal stem cells (MSC) are currently strong candidates for cell-based therapies. They are well known for their differentiation potential and immunoregulatory properties and have been proven to be potentially effective in the treatment of a large variety of diseases, including neurodegenerative disorders. Currently there is no treatment that provides consistent long-term benefits for patients with multiple system atrophy (MSA), a fatal late onset α-synucleinopathy. Principally neuroprotective or regenerative strategies, including cell-based therapies, represent a powerful approach for treating MSA. In this study we investigated the efficacy of intravenously applied MSCs in terms of behavioural improvement, neuroprotection and modulation of neuroinflammation in the (PLP)-αsynuclein (αSYN) MSA model.MSCs were intravenously applied in aged (PLP)-αSYN transgenic mice. Behavioural analyses, defining fine motor coordination and balance capabilities as well as stride length analysis, were performed to measure behavioural outcome. Neuroprotection was assessed by quantifying TH neurons in the substantia nigra pars compacta (SNc). MSC treatment on neuroinflammation was analysed by cytokine measurements (IL-1α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, GM-CSF, INFγ, MCP-1, TGF-β1, TNF-α) in brain lysates together with immunohistochemistry for T-cells and microglia. Four weeks post MSC treatment we observed neuroprotection in the SNc, as well as downregulation of cytokines involved in neuroinflammation. However, there was no behavioural improvement after MSC application.To our knowledge this is the first experimental approach of MSC treatment in a transgenic MSA mouse model. Our data suggest that intravenously infused MSCs have a potent effect on immunomodulation and neuroprotection. Our data warrant further studies to elucidate the efficacy of systemically administered MSCs in transgenic MSA models

Failure of neuroprotection by embryonic striatal grafts in a double lesion rat model of striatonigral degeneration (multiple system atrophy).

In the present experiment we studied the ability of embryonic striatal grafts to protect against striatal quinolinic acid (QA)-induced excitotoxicity in a previously established double lesion rat model of striatonigral degeneration (SND), the neuropathological substrate of parkinsonism associated with multiple system atrophy (MSA). Male Wistar rats received under halothane inhalation anesthesia a 6-hydroxydopamine 6-OHDA injection into the left medial forebrain bundle. Four to 5 weeks later apomorphine-induced rotation behavior was tested. Rats were divided into two treatment groups receiving either embryonic striatal cell suspensions or sham injections. Apomorphine-induced rotation behavior was retested 2 and 4 weeks after the grafting procedure. Following the rotation test animals of the striatal and sham graft group received a stereotaxic injection of 150 nmol QA. Again rotation behavior was assessed 2 and 4 weeks after lesioning. Brains were then processed to dopamine reuptake ([(3)H]mazindol), dopamine D1 ([(3)H]SCH23390), and D2 ([(3)H]spiperone) receptor autoradiography. Gliosis was detected using [(3)H]PK11195, a marker for peripheral benzodiazepine binding sites. Behavioral and autoradiographic analysis failed to show striatal protection in 6-OHDA prelesioned animals receiving embryonic striatal grafts. These findings indicate that beneficial protective effects of striatal grafts implanted into host striatum prior to excitotoxic insults are abolished in the presence of severe dopaminergic denervation. Our present results are relevant to future applications of neural grafting in MSA-SND

Tropism of AAV-2 vectors for neurons of the globus pallidus.

A recombinant AAV-2 vector encoding the green fluorescent protein (gfp) under the control of the cytomegalovirus (CMV) promoter was injected into the striatum at varying antero-posterior coordinates. When the virus was delivered to the anterior part of the striatum, transduction efficiency was low and limited to the vicinity of the needle tract. In contrast, after injection into the posterior part of the striatum, in addition to a localized transduced area in the striatum, efficient and widespread transduction was observed at distance from the injection site, in the globus pallidus. In the latter case, labelled cells were also detected in the internal capsule and in the stria terminalis. The number of transduced cells in the striatum increased up to I month and then decreased whereas in the globus pallidus, transduction was maximal as early as 2 weeks post-injection. In the striatum and in the globus pallidus, the labelled cells had a neuron-like morphology. In contrast, in the internal capsule, labelled cells had a glial-like morphology.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Aging of the striatum: mechanisms and interventions

Motor function declines with increasing adult age. Proper regulation of the balance between dopamine (DA) and acetylcholine (ACh) in the striatum has been shown to be fundamentally important for motor control. Although other factors can also contribute to this age-associated decline, a decrease in the concentration and binding potential of the DA D2 receptor subtype in the striatum, especially in the cholinergic interneurons, are involved in the mechanism. Our studies have shown that gene transfer of the DA D2 receptor subtype with adenoiviral vectors is effective in ameliorating age-associated functional decline of the striatal cholinergic interneurons. These achievements confirm that an age-associated decrease of D2R contributes functional alteration of the interaction of DA and ACh in the striatum and demonstrate that these age-associated changes indeed are modifiable