Vascular-directed responses of microglia produced by methamphetamine exposure: indirect evidence that microglia are involved in vascular repair?

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.

Corticosterone and exogenous glucose alter blood glucose levels, neurotoxicity, and vascular toxicity produced by methamphetamine

“…In a recent study, we found that METH results in pronounced microglia activation directed at vasculature, even in areas of the anterior medial dorsal hippocampus and lateral septum where there was no evidence of neurodegeneration or nerve terminal damage (Bowyer et al . ). We take these findings as further evidence of high glucose levels correlating with increased vascular damage.…”

“…Neurotoxic exposures to either AMPH or METH that result in severe hyperthermia produce the most damage and disruption of vasculature in the thalamus along the border between the ventral intralaminar, ventromedial and ventromedial thalamic nuclei (Bowyer et al . , ). In this region, FJc labeling of degenerating neurons is only apparent at 48 h or more after AMPH or METH exposure, while the FJc+ neurons in the parietal cortex appear within 24 h. Thus, there is indirect evidence in the thalamus that vascular damage precedes neuronal death.…”

“…In some instances, ‘cerebrovascular inflammation’ (induced primarily due to vascular damage) can occur in the brain, thereby resulting in prominent microglial activation and some moderate astrocytic morphological changes in the absence of neurodegeneration (Bowyer et al . ). While these scenarios involve concomitant neuroinflammation and neural damage, it remains unclear whether these proinflammatory responses are independent, the cause, or the consequence of toxicant‐induced neural damage (Graeber and Streit ; Streit ).…”

“…However, when life‐threatening hyperthermic events occur during exposure, substantial neuroinflammation or neurodegeneration in the parietal cortex, limbic cortex, hippocampus, and thalamus also is observed (Bowyer et al . , ). In some instances, ‘cerebrovascular inflammation’ (induced primarily due to vascular damage) can occur in the brain, thereby resulting in prominent microglial activation and some moderate astrocytic morphological changes in the absence of neurodegeneration (Bowyer et al .…”

High Morphologic Plasticity of Microglia/Macrophages Following Experimental Intracerebral Hemorrhage in Rats

“…CD68, a lysosomal activity marker expressed during inflammatory processes by microglia/macrophages, is regarded as a marker of M1 microglia/macrophages [ 13 , 17 , 18 ]. Activated microglia were reported to be labeled by CD11b immunoreactivity [ 19 ], and antibodies specific to CD206 and Ym1 are used to identify M2 microglia/macrophages [ 20 ]. In this study, it was observed that the ameboid Iba-1 positive microglia in the hemorrhagic center were CD68 positive, in brain slices taken at three days ( Figure 3 A) and even at 7, 14 and 28 days [ 21 ] after collagenase VII injection.…”