Optimizing a Rodent Model of Parkinson's Disease for Exploring the Effects and Mechanisms of Deep Brain Stimulation

Deep brain stimulation (DBS) has become a treatment for a growing number of neurological and psychiatric disorders, especially for therapy-refractory Parkinson's disease (PD). However, not all of the symptoms of PD are sufficiently improved in all patients, and side effects may occur. Further progress depends on a deeper insight into the mechanisms of action of DBS in the context of disturbed brain circuits. For this, optimized animal models have to be developed. We review not only charge transfer mechanisms at the electrode/tissue interface and strategies to increase the stimulation's energy-efficiency but also the electrochemical, electrophysiological, biochemical and functional effects of DBS. We introduce a hemi-Parkinsonian rat model for long-term experiments with chronically instrumented rats carrying a backpack stimulator and implanted platinum/iridium electrodes. This model is suitable for (1) elucidating the electrochemical processes at the electrode/tissue interface, (2) analyzing the molecular, cellular and behavioral stimulation effects, (3) testing new target regions for DBS, (4) screening for potential neuroprotective DBS effects, and (5) improving the efficacy and safety of the method. An outlook is given on further developments of experimental DBS, including the use of transgenic animals and the testing of closed-loop systems for the direct on-demand application of electric stimulation

A proinflammatory role for Fas in joints of mice with collagen-induced arthritis

Collagen-induced arthritis (CIA) is a chronic inflammatory disease bearing all the hallmarks of rheumatoid arthritis, e.g. polyarthritis, synovitis, and subsequent cartilage/bone erosions. One feature of the disease contributing to joint damage is synovial hyperplasia. The factors responsible for the hyperplasia are unknown; however, an imbalance between rates of cell proliferation and cell death (apoptosis) has been suggested. To evaluate the role of a major pathway of cell death – Fas (CD95)/FasL – in the pathogenesis of CIA, DBA/1J mice with a mutation of the Fas gene (lpr) were generated. The susceptibility of the mutant DBA-lpr/lpr mice to arthritis induced by collagen type II was evaluated. Contrary to expectations, the DBA-lpr/lpr mice developed significantly milder disease than the control littermates. The incidence of disease was also significantly lower in the lpr/lpr mice than in the controls (40% versus 81%; P < 0.05). However DBA-lpr/lpr mice mounted a robust immune response to collagen, and the expression of local proinflammatory cytokines such as, e.g., tumor necrosis factor α (TNF-α) and IL-6 were increased at the onset of disease. Since the contribution of synovial fibroblasts to inflammation and joint destruction is crucial, the potential activating effect of Fas on mouse fibroblast cell line NIH3T3 was investigated. On treatment with anti-Fas in vitro, the cell death of NIH3T3 fibroblasts was reduced and the expression of proinflammatory cytokines TNF-α and IL-6 was increased. These findings suggest that impairment of immune tolerance by increased T-cell reactivity does not lead to enhanced susceptibility to CIA and point to a role of Fas in joint destruction

Perforin deficiency attenuates collagen-induced arthritis

Collagen-induced arthritis (CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8(+ )T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8(+ )T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp(-/-), and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp(+/+), 64%; DBA/1J-pfp(-/-), 54%), a slightly delayed onset (onset of disease: DBA/1J-pfp(+/+), 53 ± 3.6; DBA/1J-pfp(-/-), 59 ± 4.9 (mean ± SEM), and milder form of the disease (maximum disease score: DBA/1J-pfp(+/+), 7.3 ± 1.1; DBA/1J-pfp(-/-), 3.4 ± 1.4 (mean ± SEM); P < 0.05). Concomitantly, peripheral T cell proliferation in response to the specific antigen bovine collagen II was increased in pfp(-/- )mice compared with pfp(+/+ )mice, arguing for an impaired killing of autoreactive T cells caused by pfp deficiency. Thus, pfp-mediated cytotoxicity is involved in the initiation of tissue damage in arthritis, but pfp-independent cytotoxic death pathways might also contribute to CIA

Attenuated EAN in TNF-α Deficient Mice Is Associated with an Altered Balance of M1/M2 Macrophages

The role of tumor necrosis factor (TNF)-α and its receptors in neuroautoimmune and neuroinflammatory diseases has been controversial. On the basis of our previous studies, we hereby aimed to further clarify TNF-α’s mechanism of action and to explore the potential role of TNF-α receptor (TNFR)1 as a therapeutic target in experimental autoimmune neuritis (EAN). EAN was induced by immunization with P0 peptide 180–199 in TNF-α knockout (KO) mice and anti-TNFR1 antibodies were used to treat EAN. Particularly, the effects of TNF-α deficiency and TNFR1 blockade on macrophage functions were investigated. The onset of EAN in TNF-α KO mice was markedly later than that in wild type (WT) mice. From day 14 post immunization, the clinical signs of TNF-α KO mice were significantly milder than those of their WT counterparts. Further, we showed that the clinical severity of WT mice treated with anti-TNFR1 antibodies was less severe than that of the control WT mice receiving PBS. Nevertheless, no difference with regard to the clinical signs of EAN or inflammatory infiltration in cauda equina was seen between TNF-α KO and WT mice with EAN after blockade of TNFR1. Although TNF-α deficiency did not alter the proliferation of lymphocytes in response to either antigenic or mitogenic stimuli, it down-regulated the production of interleukin (IL)-12 and nitric oxide (NO), and enhanced the production of IL-10 in macrophages. Increased ratio of regulatory T cells (Tregs) and reduced production of interferon (IFN)-γ in cauda equina infiltrating cells, and elevated levels of IgG2b antibodies against P0 peptide 180–199 in sera were found in TNF-α KO mice with EAN. In conclusion, TNF-α deficiency attenuates EAN via altering the M1/M2 balance of macrophages

Kainic acid-induced microglial activation is attenuated in aged interleukin-18 deficient mice

Abstract Background Previously, we found that interleukin (IL)-18 deficiency aggravates kainic acid (KA)-induced hippocampal neurodegeneration in young C57BL/6 mice due to an over-compensation by IL-12. Additionally, IL-18 participates in fundamental inflammatory processes that increase during aging. In the present study, we were interested in the role of IL-18 in KA-induced neurodegeneration in aged female C57BL/6 mice. Methods Fifteen aged female IL-18 knockout (KO) and 15 age-matched wild-type (WT) mice (18 to 19 months old) were treated with KA at a dose of 25 mg/kg body weight intranasally. Seizure activities and behavioral changes were rated using a 6-point scoring system and open-field test, respectively. Seven days after KA treatment, degenerating neurons were detected by Nissl's method and Fluoro-Jade B staining; and microglial activation was analyzed by immunohistochemistry and flow cytometry. Results Aged female IL-18 KO and WT mice showed similar responses to treatment with KA as demonstrated by comparable seizure activities, behavioral changes and neuronal cell death. However, aged female IL-18 KO mice failed to exhibit the strong microglial activation shown in WT mice. Interestingly, even though the number of activated microglia was less in KA-treated IL-18 KO mice than in KA-treated WT mice, the proportion of microglia that expressed the cytokines tumor necrosis factor (TNF)-α, IL-6 and IL-10 was higher in KA-treated IL-18 KO mice. Conclusion Deficiency of IL-18 attenuates microglial activation after KA-induced excitotoxicity in aged brain, while the net effects of IL-18 deficiency are balanced by the enhancement of other cytokines, such as TNF-α, IL-6 and IL-10.</p