Down-regulation of microglial activity attenuates axotomized nigral dopaminergic neuronal cell loss

Abstract

BackgroundThere is growing evidence that inflammatory processes of activated microglia could play an important role in the progression of nerve cell damage in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease which harbor features of chronic microglial activation, though the precise mechanism is unknown. In this study, we presented in vivo and ex vivo experimental evidences indicating that activated microglia could exacerbate the survival of axotomized dopaminergic neurons and that appropriate inactivation of microglia could be neuroprotective.ResultsThe transection of medial forebrain bundle (MFB) of a rat induced loss of dopaminergic neurons in a time-dependent manner and accompanied with microglial activation. Along with microglial activation, production of reactive oxygen species (ROS) was upregulated and TH/OX6/hydroethidine triple-immunofluorescence showed that the microglia mainly produced ROS. When the activated microglial cells that were isolated from the substantia nigra of the MFB axotomized animal, were transplanted into the substantia nigra of which MFB had been transected at 7 days ago, the survival rate of axotomized dopaminergic neurons was significantly reduced as compared with sham control. Meanwhile, when the microglial activation was attenuated by administration of tuftsin fragment 1-3 (microglia inhibitory factor) into the lateral ventricle using mini-osmotic pump, the survival rate of axotomized dopaminergic neurons was increased.ConclusionThe present study suggests that activated microglia could actively produce and secrete unfavorable toxic substances, such as ROS, which could accelerate dopaminergic neuronal cell loss. So, well-controlled blockade of microglial activation might be neuroprotective in some neuropathological conditions.

Changes of gene expression of Gal3, Hsp27, Lcn2, and Timp1 in rat substantia nigra following medial forebrain bundle transection using a candidate gene microarray

“…It has been suggested that neuroglial activator(s) could be involved in the pathogenesis of neurodegenerative disease. This hypothesis is supported by our most recent finding that activated microglia could actively produce and secrete unfavorable toxic substances, such as reactive oxygen species (ROS), and that the well-controlled blockade of microglial activation increase collateral neuronal survival (Song et al, 2013). These findings strongly suggest that activated neuroglia play an important role in the early stage of disease pathogenesis.…”

“…These successive events are likely to promote clustering of neuroglia around SN and may elicit irreversible neuronal dysfunction, which might cause the eventual death of vulnerable neuronal populations and dopaminergic neurons in the SN (Tansey and Goldberg, 2010). In a previous report (Song et al, 2013), we presented experimental data indicating that highly activated microglia could lead to neurotoxicity to axotomized DA neurons by producing reactive oxygen species (ROS). We also demonstrated that appropriate blockade or microglial activation could be neuroprotective (Song et al, 2013).…”

“…To investigate whether target proteins were expressed in SN, immunohistochemistry was performed as described previously (Song et al, 2013). Briefly, 1, 3, 7, and 14 days after unilateral MFB transection, animals were deeply anesthetized and perfused transcardially with 200 ml ice-cold 4% paraformaldehyde in 0.1 M phosphate buffer.…”

“…This MFB transection model in the adult rat leads to different degrees and rates of DA neuronal death, inducing neuroglial activation in a time-dependent manner. Therefore, the MFB transection model is a suitable animal model for DA neuronal degeneration and neuroglial activity (Song et al, 2013).…”

Lipoic acid protects dopaminergic neurons in LPS-induced Parkinson’s disease model

“…*P < 0.05; **P < 0.01, ***P < 0.001 as that created by inflammation, could result in neuronal death in cells with high cytosolic calcium levels, suggesting that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. (Song et al 2013) It has been previously reported that intra-nigral and intra-striatal administration of LPS induced symptoms of PD, dopaminergic neuron death, and microglial activation (He et al 2013;Dutta et al 2008;Liu and Bing 2011;Tanaka et al 2013). We have recently demonstrated that i.n.…”