Biology subjects

Zbesko, J. C.

Publications and source records attributed to Zbesko, J. C..

3 recordsLinked to original sources

bioRxiv2021

Repeated administration of 2-hydroxypropyl-β-cyclodextrin (HPβCD) attenuates the chronic inflammatory response to experimental stroke

Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that may contribute to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-hydroxypropyl-{beta}-cyclodextrin (HP{beta}CD) is an FDA-approved cyclic oligosaccharide that can solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HP{beta}CD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we subcutaneously injected young adult and aged male mice with vehicle or HP{beta}CD three times per week, with treatment beginning one week after stroke. We evaluated mice at 7 weeks following stroke using immunostaining, RNA sequencing, lipidomics, and behavioral analyses. Chronic stroke infarct and peri-infarct regions of HP{beta}CD-treated mice were characterized by an upregulation of genes involved in lipid metabolism and a downregulation of genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, HP{beta}CD reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HP{beta}CD also preserved NeuN immunoreactivity in the striatum and thalamus and c-Fos immunoreactivity in hippocampal regions. Additionally, HP{beta}CD improved recovery through the protection of hippocampal-dependent spatial working memory and reduction of impulsivity. These results indicate that systemic HP{beta}CD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents post-stroke cognitive decline. Significance StatementDementia is a common and debilitating sequela of stroke. Currently, there are no available treatments for post-stroke dementia. Our study shows that lipid metabolism is disrupted in chronic stroke infarcts, which causes an accumulation of uncleared lipid debris and correlates with a chronic inflammatory response. To our knowledge, these substantial changes in lipid homeostasis have not been previously recognized or investigated in the context of ischemic stroke. We also provide a proof of principle that solubilizing and entrapping lipophilic substances using HP{beta}CD could be an effective strategy for treating chronic inflammation after stroke and other CNS injuries. We propose that using HP{beta}CD for the prevention of post-stroke dementia could improve recovery and increase long-term quality of life in stroke sufferers.

neuroscience↗

bioRxiv2021

Post-stroke administration of the p75 neurotrophin receptor modulator, LM11A-31, attenuates chronic changes in brain metabolism, increases neurotransmitter levels, and improves recovery

The aim of this study was to test whether post-stroke oral administration of a small molecule p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle treated mice by principal component analysis and had higher levels of serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks following stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31 treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31 treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nest construction test, and less impulsivity in an open field test. These data support small molecule modulation of the p75 neurotrophin receptor for preserving neuronal health and function during stroke recovery. SIGNIFICANCE STATEMENTThe findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimers disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.

neuroscience↗

bioRxiv2018

Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin dependent mechanism

Here we used mouse models of heart and brain ischemia to compare the inflammatory response to ischemia in the heart, a protein rich organ, to the inflammatory response to ischemia in the brain, a lipid rich organ. We report that ischemia-induced inflammation resolves between 1 and 4 weeks in the heart compared to between 8 and 24 weeks in the brain. Importantly, we discovered that a second burst of inflammation occurs in the brain between 4 and 8 weeks following ischemia, which coincided with the appearance of cholesterol crystals within the infarct. This second wave shares a similar cellular and molecular profile with atherosclerosis and is characterized by high levels of osteopontin (OPN) and matrix metalloproteinases (MMPs). In order to test the role of OPN in areas of liquefactive necrosis, OPN-/- mice were subjected to brain ischemia. We found that at 7 weeks following stroke, the expression of pro-inflammatory proteins and MMPs was profoundly reduced in the infarct of the OPN-/- mice, although the number of cholesterol crystals was increased. OPN-/- mice exhibited faster recovery of motor function and a higher number of neuronal nuclei (NeuN) positive cells in the peri-infarct area at 7 weeks following stroke. Based on these findings we propose that the brain liquefies after stroke because phagocytic cells in the infarct are unable to efficiently clear cholesterol rich myelin debris, and that this leads to the perpetuation of an OPN-dependent inflammatory response characterized by high levels of degradative enzymes.\n\nSignificance StatementThe inflammatory response to ischemia in the brain is different to the response to ischemic injury in other organs. In the brain, and for unknown reasons, dead tissue liquefies in response to ischemia by the process of liquefactive necrosis. However, the data we present here demonstrate that there is overlap between the pathophysiology of liquefactive necrosis and atherosclerosis. Specifically, we show that chronic stroke infarcts contain foamy macrophages, cholesterol crystals, high levels of OPN and MMPs, and a similar cytokine profile to atherosclerosis. Therefore, because cholesterol is a central component of myelin, liquefactive necrosis in response to stroke may be caused by an inflammatory response to cholesterol-rich myelin debris that is driven in large part by OPN and MMPs.

neuroscience↗