Glial cells, including astrocytes and microglia, are pivotal in maintaining central nervous system (CNS) homeostasis and responding to pathological insults. This review elucidates the complex immunomodulatory functions of glial cells, with a particular focus on their involvement in inflammation cascades initiated by the accumulation of alpha-synuclein (α-syn), a hallmark of Parkinson’s disease (PD). Deriving insights from studies on both sporadic and familial forms of PD, as well as animal models of PD, we explore how glial cells contribute to the progression of inflammation triggered by α-syn aggregation. Additionally, we analyze the interplay between glial cells and the blood-brain barrier (BBB), highlighting the role of these cells in maintaining BBB integrity and permeability in the context of PD pathology. Furthermore, we delve into the potential activation of repair and neuroprotective mechanisms mediated by glial cells amidst α-syn-induced neuroinflammation. By integrating information on sporadic and familial PD, as well as BBB dynamics, this review aims to deepen our understanding of the multifaceted interactions between glial cells, α-syn pathology, and CNS inflammation, thereby offering valuable insights into therapeutic strategies for PD and related neurodegenerative disorders.

Deep brain stimulation of the subthalamic nucleus (DBS-STN) is an effective treatment for advanced motor symptoms of Parkinson’s disease (PD). Recently, a connection between the limbic part of the STN and side effects of DBS-STN has been increasingly recognized. Animal studies have shown that DBS-STN influences behavior and provokes neurochemical changes in regions of the limbic system. Some of these regions, which are activated during DBS-STN, are involved in neuroimmunomodulation. The therapeutic effects of DBS-STN in PD treatment are clear, but the influence of DBS-STN on peripheral immunity has not been reported so far. In this study, we examined the effects of unilateral DBS-STN applied in male Wistar rats with 6-hydroxydopamine PD model (DBS-6OHDA) and rats without nigral dopamine depletion (DBS) on corticosterone (CORT) plasma concentration, blood natural killer cell cytotoxicity (NKCC), leukocyte numbers, lymphocyte population and apoptosis numbers, plasma interferon gamma (IFN-γ), interleukin 6 (IL-6), and tumor necrosis factor (TNF-α) concentration. The same peripheral immune parameters we measured also in non-stimulated rats with PD model (6OHDA). We observed peripheral immunity changes related to PD model. The NKCC and percentage of T cytotoxic lymphocytes were enhanced, while the level of lymphocyte apoptosis was down regulated in 6OHDA and DBS-6OHDA groups. After DBS-STN (DBS-6OHDA and DBS groups), the plasma CORT and TNF-α were elevated, the number of NK cells and percentage of apoptosis were increased, while the number of B lymphocytes was decreased. We also found, changes in plasma IFN-γ and IL-6 levels in all the groups. These results suggest potential peripheral immunomodulative effects of DBS-STN in the rat model of PD. However, further studies are necessary to explain these findings and their clinical implication.

Purpose: Intracerebroventricular-(ICV)-streptozotocin-(STZ)-induced neuroinflammation is a model of Alzheimer’s disease (AD) compatible with the inflammation hypothesis of ageing (“inflammaging” state). Previously, we observed age-dependent (young vs aged) dimethyl fumarate (DMF)-induced anti-inflammatory and neuroprotective effects in the brain along with improvement in cognitive functions in rats with the ICV-STZ-induced model of AD. To evaluate whether DMF reduces neuroinflammation based on the peripheral inflammatory response inhibition, we determined peripheral inflammatory mediators in young and aged rats with the ICV-STZ-induced AD pathology following DMF therapy. Materials and Methods: Young (4-month-old) and aged (22-month-old) rats were fed with 0.4% DMF rat chow for 21 consecutive days after ICV-STZ (3 mg/ventricle) injections. After behavioral testing, blood and spleens were collected to determine the numbers of leukocytes (WBC), lymphocytes and their subpopulations, haematological parameters, the concanavalin (Con)-A-induced production and plasma concentration of interferon (IFN)-γ, interleukin (IL)-6, IL-10 and corticosterone (COR). Results: Age-dependent anti-inflammatory effect of the DMF treatment in rats with ICV-STZ injections manifested as decreased peripheral WBC and lymphocyte numbers, including TCD3⁺CD4⁺CD8⁻, TCD3⁺CD4⁻CD8⁺, B (CD45RA⁺) and NK (161a⁺), in aged rats. Furthermore, DMF lowered the blood and spleen lymphocyte production of pro-inflammatory IFN-γ and IL-6 in young and aged rats, whereas it enhanced the plasma level of anti-inflammatory IL-10 and lymphocyte’s ability to produce it in aged rats only. In parallel to changes in peripheral WBC numbers in the model of AD, DMF decreased the red blood cell number, haemoglobin concentration, haematocrit and mean platelet volume in aged, but not young, rats. In contrast to controls, DMF did not influence the COR response in STZ groups. Conclusion: Besides preventing neuroinflammation, DMF acts on the pro-/anti-inflammatory balance in the periphery and causes an anti-inflammatory shift in T lymphocytes which could contribute to DMF’s therapeutic effects in the ICV-STZ-induced model of AD, in particular, in aged rats.