Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6‐hydroxydopamine model of Parkinson’s disease

Abstract

Cellular interactions between activated microglia and degenerating neurons in in vivo models of Parkinson’s disease are not well defined. This time course study assesses the dynamics of morphological and immunophenotypic properties of activated microglia in a 6‐hydroxydopamine (6‐OHDA) model of Parkinson’s disease. Neurodegeneration in the substantia nigra pars compacta (SNc) was induced by unilateral injection of 6‐OHDA into the medial forebrain bundle. Activated microglia, identified using monoclonal antibodies: clone of antibody that detects major histocompatibility complex (MHC) class II antigens (OX6) for MHC class II, clone of antibody that detects cell surface antigen‐cluster of differentiation 11b – anti‐complement receptor 3, a marker for complement receptor 3 and CD 68 for phagocytic activity. Activation of microglia in the lesioned SNc was rapid with cells possessing amoeboid or ramified morphology appeared on day 1, whilst antibody clone that detects macrophage‐myeloid associated antigen immunoreactivity was observed at day 3 post‐lesion when there was no apparent loss of tyrosine hydroxylase (TH)+ve dopaminergic (DA) SNc neurons. Thereafter, OX6 and antibody clone that detects macrophage‐myeloid associated antigen activated microglia selectively adhered to degenerating axons, dendrites and apoptotic (caspase 3+ve) DA neurons in the SNc were observed at day 7. This was followed by progressive loss of TH+ve SNc neurons, with the peak of TH+ve cell loss (51%) being observed at day 9. This study suggests that activation of microglia precedes DA neuronal cell loss and neurons undergoing degeneration may be phagocytosed prematurely by phagocytic microglia.

Progressive changes of orexin system in a rat model of 6-hydroxydopamineinduced Parkinson’s disease

“…The time point of half loss was estimated to be approximately at day 9 or 10. This dynamic change of TH neurons after administration of 6-OHDA into MFB is consistent with a previous report [14] . In comparison with this rapid loss of TH neurons, the number of orexin-A neurons started to decrease only at day 21 after surgery, and at day 49, the neuronal loss was about 30%.…”

“…MFB is composed of projecting axonal fibers from SN to the striatum. Injection of 6-OHDA to MFB could also cause rapid cell degeneration, and the half loss appears within the first 10 d [14] . Apart from the morphological loss of TH neurons, the rats subject to these 2 operations also develop obvious hypokinesia within the first 21 d.…”

Dual Role of Superoxide Dismutase 2 Induced in Activated Microglia

“…Notably, neuroinflammation is closely linked to the onset and/or development of these CNS diseases (1)(2)(3)(4)(5). Considering these reports and our findings, SOD2 mutations may induce diverse CNS diseases due to excessive or prolonged microglial activation and subsequent neuroinflammation.…”

“…#, p Ͻ 0.05; ##, p Ͻ 0.01 versus the LPS-treated group carrying control siRNA. disorders, including neurodegenerative diseases and epilepsy (1)(2)(3)(4)(5), this mechanism for controlling the activity of microglia may effectively maintain immune homeostasis in the CNS.…”

“…However, excessive activation of microglia may be harmful to host cells; for example, microglia can promote the development of various neuronal diseases by producing large amounts of inflammatory molecules, such as tumor necrosis factor-␣ (TNF␣), interleukin-1␤ (IL-1␤), and reactive oxygen species (ROS). 2 Indeed, microglia with abnormal activity reportedly induce neuroinflammation and are implicated in the pathogenesis of Parkinson disease, Alzheimer disease, brain ischemia-reperfusion injury, trauma, epilepsy, depression, and schizophrenia (1)(2)(3)(4)(5). Therefore, understanding the mechanisms that control the microglial activity is critical, not only for comprehending the physiology of microglia but also for developing new therapeutic approaches to treating neuroinflammation and/or neurodegenerative diseases.…”