Abstract
BackgroundBrain microglial activations and damage responses are most commonly associated with neurodegeneration or systemic innate immune system activation. Here, we used histological methods to focus on microglial responses that are directed towards brain vasculature, previously undescribed, after a neurotoxic exposure to methamphetamine.MethodsMale rats were given doses of methamphetamine that produce pronounced hyperthermia, hypertension, and toxicity. Identification of microglia and microglia-like cells (pericytes and possibly perivascular cells) was done using immunoreactivity to allograft inflammatory factor 1 (Aif1 a.k.a Iba1) and alpha M integrin (Itgam a.k.a. Cd11b) while vasculature endothelium was identified using rat endothelial cell antigen 1 (RECA-1). Regions of neuronal, axonal, and nerve terminal degeneration were determined using Fluoro-Jade C.ResultsDual labeling of vasculature (RECA-1) and microglia (Iba1) showed a strong association of hypertrophied cells surrounding and juxtaposed to vasculature in the septum, medial dorsal hippocampus, piriform cortex, and thalamus. The Iba1 labeling was more pronounced in the cell body while Cd11b more so in the processes of activated microglia. These regions have been previously identified to have vascular leakage after neurotoxic methamphetamine exposure. Dual labeling with Fluoro-Jade C and Iba1 indicated that there was minimal or no evidence of neuronal damage in the septum and hippocampus where many hypertrophied Iba1-labeled cells were found to be associated with vasculature. Although microglial activation around the prominent neurodegeneration was found in the thalamus, there were also many examples of activated microglia associated with vasculature.ConclusionsThe data implicate microglia, and possibly related cell types, in playing a major role in responding to methamphetamine-induced vascular damage, and possibly repair, in the absence of neurodegeneration. Identifying brain regions with hypertrophied/activated microglial-like cells associated with vasculature has the potential for identifying regions of more subtle examples of vascular damage and BBB compromise.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0526-6) contains supplementary material, which is available to authorized users.
Highlights
Brain microglial activations and damage responses are most commonly associated with neurodegeneration or systemic innate immune system activation
Microglial responses to METH and amphetamine (AMPH) damage to dopaminergic axons and nerve terminals in the striatum [9, 10] and neurodegeneration in the parietal cortex, thalamus, and hippocampus and other limbic regions [11,12,13] were first identified over 20 years ago
The simplest and, in our opinion, the most logical explanation for the presence of activated microglia surrounding the vasculature in two discrete regions of the brain where there is no neurodegeneration would be that the microglia are responding to METH-induced vascular damage
Summary
Brain microglial activations and damage responses are most commonly associated with neurodegeneration or systemic innate immune system activation. It has been shown that microglia are not involved in producing or exacerbating the neurodegeneration, but responding to it [2, 3, 11,12,13] This has been observed for dopaminergic terminal damage in the striatum due to amphetamines or MPTP [14,15,16]. It was shown that you can block the microglial response without affecting the degree of neurodegeneration, indicating parallel processes [14]. It has been known for some time that microglia play a role in scavenging degenerating neurons [17]. The origin and development of microglia in the brain has been elucidated [18], the role of microglia in disease and the neurotoxic process is continually being reevaluated and debated [8, 14, 19,20,21,22,23]
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