scholarly journals Determining the effect of aging, recovery time, and post-stroke memantine treatment on delayed thalamic gliosis after cortical infarct

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gab Seok Kim ◽  
Jessica M. Stephenson ◽  
Abdullah Al Mamun ◽  
Ting Wu ◽  
Monica G. Goss ◽  
...  
Keyword(s):  
Neuronal Loss ◽  
Secondary Injury ◽  
Age Dependency ◽  
Delayed Treatment ◽  
Aged Mice ◽  
Post Stroke ◽  
Memantine Treatment ◽  
Cortical Stroke ◽  
Effects Of Aging ◽  
Distal Middle Cerebral Artery

AbstractSecondary injury following cortical stroke includes delayed gliosis and eventual neuronal loss in the thalamus. However, the effects of aging and the potential to ameliorate this gliosis with NMDA receptor (NMDAR) antagonism are not established. We used the permanent distal middle cerebral artery stroke model (pdMCAO) to examine secondary thalamic injury in young and aged mice. At 3 days post-stroke (PSD3), slight microgliosis (IBA-1) and astrogliosis (GFAP) was evident in thalamus, but no infarct. Gliosis increased dramatically through PSD14, at which point degenerating neurons were detected. Flow cytometry demonstrated a significant increase in CD11b+/CD45int microglia (MG) in the ipsilateral thalamus at PSD14. CCR2-RFP reporter mouse further demonstrated that influx of peripheral monocytes contributed to the MG/Mϕ population. Aged mice demonstrated reduced microgliosis and astrogliosis compared with young mice. Interestingly, astrogliosis demonstrated glial scar-like characteristics at two years post-stroke, but not by 6 weeks. Lastly, treatment with memantine (NMDAR antagonist) at 4 and 24 h after stroke significantly reduced gliosis at PSD14. These findings expand our understanding of gliosis in the thalamus following cortical stroke and demonstrate age-dependency of this secondary injury. Additionally, these findings indicate that delayed treatment with memantine (an FDA approved drug) provides significant reduction in thalamic gliosis.

scholarly journals Cortical Stroke Produces Secondary Injury and Long-lasting Gliosis in the Ipsilateral Thalamus

2021 ◽  
Author(s):  
Gab Seok Kim ◽  
Jessica Stephenson ◽  
Abdullah Al Mamun ◽  
Ting Wu ◽  
Monica Goss ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Progressive Increase ◽  
Nmda Receptor Antagonist ◽  
Secondary Injury ◽  
Stroke Model ◽  
Stroke Treatment ◽  
Post Stroke ◽  
Memantine Treatment ◽  
Cortical Stroke

Abstract Remote secondary injury in the thalamus has been observed following cortical infarct, however the mechanisms are not well understood. We used the distal MCAO stroke model (pdMCAO) to explore the cellular and temporal gliosis response in secondary thalamic injury in mice. At 3 days post-stroke (PSD3), primary infarct was limited to the cortex, with no infarct in the thalamus. However, at 2 weeks after stroke (PSD14), the ipsilateral thalamus demonstrated degenerating and severely damaged neurons. Staining for GFAP (astrogliosis) or IBA-1 (microgliosis) was first apparent in the ipsilateral thalamus by PSD3, and showed a progressive increase through PSD14. The number of activated microglia was increased within the thalamus at PSD14, reflecting proliferation of resident microglia as well as infiltration of peripheral monocytes. Interestingly, astrogliosis within the thalamus was enduring, as it was still evident at two years post-stroke. Furthermore, the astrogliosis at two years (but not at 6 weeks) demonstrated glial scar-like characteristics. Lastly, we demonstrated that post-stroke treatment with an NMDA receptor antagonist (memantine) reduces gliosis in the thalamus at PSD14. These findings highlight the development of lasting secondary injury in the thalamus following cortical stroke and support the value of memantine treatment in the mitigation of this injury.

scholarly journals Cortical stroke produces secondary injury and long-lasting gliosis in the ipsilateral thalamus

2020 ◽  
Author(s):  
Gab Seok Kim ◽  
Jessica M. Stephenson ◽  
Abdullah Al Mamun ◽  
Ting Wu ◽  
Monica G. Goss ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Progressive Increase ◽  
Nmda Receptor Antagonist ◽  
Secondary Injury ◽  
Stroke Model ◽  
Stroke Treatment ◽  
Post Stroke ◽  
Memantine Treatment ◽  
Cortical Stroke

AbstractRemote secondary injury in the thalamus has been observed following cortical infarct, however the mechanisms are not well understood. We used the distal MCAO stroke model (pdMCAO) to explore the cellular and temporal gliosis response in secondary thalamic injury in mice. At 3 days post-stroke (PSD3), primary infarct was limited to the cortex, with no infarct in the thalamus. However, at 2 weeks after stroke (PSD14), the ipsilateral thalamus demonstrated degenerating and severely damaged neurons. Staining for GFAP (astrogliosis) or IBA-1 (microgliosis) was first apparent in the ipsilateral thalamus by PSD3, and showed a progressive increase through PSD14. The number of activated microglia was increased within the thalamus at PSD14, reflecting proliferation of resident microglia as well as infiltration of peripheral monocytes. Interestingly, astrogliosis within the thalamus was enduring, as it was still evident at two years post-stroke. Furthermore, the astrogliosis at two years (but not at 6 weeks) demonstrated glial scar-like characteristics. Lastly, we demonstrated that post-stroke treatment with an NMDA receptor antagonist (memantine) reduces gliosis in the thalamus at PSD14. These findings highlight the development of lasting secondary injury in the thalamus following cortical stroke and support the value of memantine treatment in the mitigation of this injury.

Abstract P736: Memantine, an NMDA Antagonist and Aging Alter the Thalamic Gliosis in Experimental Stroke in Mice

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Gab Seok Kim ◽  
Jessica Stephenson ◽  
Ting Wu ◽  
Abdullah Mamun ◽  
Monica G Goss ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Time Course ◽  
Nmda Antagonist ◽  
Cresyl Violet ◽  
Experimental Stroke ◽  
Secondary Injury ◽  
Post Stroke ◽  
Cortical Infarction ◽  
Cortical Stroke ◽  
Young Mice

Secondary injury in the thalamus has been observed following cortical stroke in rodents and humans and is associated with worsened recovery. Interruption of this progressive injury reflects an important therapeutic goal. However, the mechanisms whereby primary cortical infarction leads to remote injury in distant regions of brain are not well defined. We used a mouse model of cortical stroke (which demonstrates delayed thalamic injury) to define the time course of thalamic gliosis and neuronal injury and then test the potential of delayed memantine treatment (an NMDA receptor antagonist) to attenuate this secondary injury. Methods: Cortical infarction was induced by permanent occlusion of the distal middle cerebral artery (pdMCAO) in male C57BL/6J mice (young and aged) and CCR2-RFP mice. Brain infarct, cell-specific injury, and gliosis were measured by cresyl violet, Fluoro-jade C (FJC), TTC, FACS, and immunofluorescence. In young mice, memantine was injected at 4 and 24 hours post-stroke (100 and 50 mg/kg, ip). Brains were evaluated at post-stroke day 3 and 14 (PSD3 and PSD14). Results: At PSD3, the primary infarct was restricted to the cortex of the MCA territory, with no infarct detected in the thalamus of young mice. However, by PSD 14, neurons in the ipsilateral thalamus exhibited significant injury (FJC positive, condensed pyknotic nuclei). Gliosis was first detectable in the ipsilateral thalamus at PSD3 and progressively increased to PSD14 (anti-GFAP and Iba1). Infiltration of peripheral-derived monocytes was determined to be one source of the activated microglia in the thalamus (CCR2-RFP reporter mice, n=3). Interestingly, pdMCAO mice allowed to recover for two years demonstrated persistent astrogliosis (cortex and thalamus), though microgliosis was no longer evident (n=2). Aged mice subjected to pdMCAO also demonstrated gliosis in thalamus at PSD14, albeit to a lesser extent than young mice (n=5 each age). Finally, delayed treatment with memantine resulted in significantly attenuated gliosis and neuronal loss in the thalamus at PSD14 (young mice, n=9 each). Conclusions: These results further define gliosis in the mechanism of secondary injury and importantly demonstrate attenuation of secondary injury by delayed NMDA receptor antagonism.

More than motor impairment: A spatiotemporal analysis of cognitive impairment and associated neuropathological changes following cortical photothrombotic stroke

2021 ◽  
pp. 0271678X2110058
Author(s):  
Sonia Sanchez-Bezanilla ◽  
Rebecca J Hood ◽  
Lyndsey E Collins-Praino ◽  
Renée J Turner ◽  
Frederick R Walker ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Motor Impairment ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Spatiotemporal Analysis ◽  
Motor Recovery ◽  
Experimental Stroke ◽  
Post Stroke ◽  
Cortical Stroke ◽  
Photothrombotic Stroke

There is emerging evidence suggesting that a cortical stroke can cause delayed and remote hippocampal dysregulation, leading to cognitive impairment. In this study, we aimed to investigate motor and cognitive outcomes after experimental stroke, and their association with secondary neurodegenerative processes. Specifically, we used a photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Motor function was assessed using the cylinder and grid walk tasks. Changes in cognition were assessed using a mouse touchscreen platform. Neuronal loss, gliosis and amyloid-β accumulation were investigated in the peri-infarct and ipsilateral hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed persistent impairment in cognitive function post-stroke, whilst there was a modest spontaneous motor recovery over the investigated period of 84 days. In the peri-infarct region, we detected a reduction in neuronal loss and decreased neuroinflammation over time post-stroke, which potentially explains the spontaneous motor recovery. Conversely, we observed persistent neuronal loss together with concomitant increased neuroinflammation and amyloid-β accumulation in the hippocampus, which likely accounts for the persistent cognitive dysfunction. Our findings indicate that cortical stroke induces secondary neurodegenerative processes in the hippocampus, a region remote from the primary infarct, potentially contributing to the progression of post-stroke cognitive impairment.

Abstract W MP50: Pair Housing Reverses the Detrimental Effect of Social Isolation and Restores BDNF and MBP in Aged Mice after Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Rajkumar Verma ◽  
Nia Harris ◽  
Brett Friedler ◽  
Joshua Crapser ◽  
Anita Patel ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Western Blot ◽  
Social Isolation ◽  
Enhanced Recovery ◽  
Infarct Volume ◽  
Recognition Task ◽  
Aged Mice ◽  
Post Stroke ◽  
Beneficial Effects ◽  
Novel Object Recognition Task

Background: Age is an important non-modifiable risk factor for stroke. Stroke rates double every decade after age 55. Social isolation (SI) exacerbates behavioural deficits, slows functional recovery and worsens histological injury after stroke in young animals, primarily by increasing the inflammatory response. However, the inflammatory response differs in aging, and whether the detrimental effects of SI are seen in aged animals is unknown. We hypothesize that acute and chronic post stroke SI will worsen stroke pathology and recovery in aged mice and pair housing (PH) will reverse these effects. Methods: Eighteen-month-old male C57BL/6 mice were pair housed (PH) for two weeks prior to stroke and randomly assigned to various housing conditions immediately after stroke. Behavioral analysis was done weekly starting at day 7. Mice were sacrificed either at 72 hours or 4 weeks after 60-minute right MCAO or sham surgery (n=9-10/group). Results: Mice isolated after stroke (ST-ISO) mice had significantly greater hemispheric infarct volume and neurological deficit scores (p<.05. n=13/group) than pair-housed (PH) stroke mice at 72 hours. SI mice that were isolated immediately after stroke showed significantly higher plasma IL-6 levels compared to PH sham (P<.001, n=13/group ) or PH stroke mice (P<.05) after 72 hour, but levels were similar by 4 weeks post-stroke (n=9-14/group). No change in tissue atrophy was seen after 4 weeks, however a significant interaction [F (1, 28) = 259.6, P<0.001] between housing and stroke was found in the Novel Object Recognition Task (NORT) at day 14. PH led to increased expression of Brain-derived neurotrophic factor (BDNF) and myelin basic protein (MBP) by IHC and western blot (n=5/group for IHC and n= 4/ western blot). Conclusions: Social isolation immediately after stroke led to enhanced injury acutely. Despite similar infarcts at 4 weeks, SI mice had delayed behavioral recovery. Pair housing led to increased expression of BDNF and myelin protein expression. Therefore, the beneficial effects of pair housing may be related to BDNF and MBP expression and enhanced recovery after injury in aged animals.

Abstract 65: Restoration of Growth Differentiation Factor 11 Protects Against Stroke in Mice

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Anjali Chauhan ◽  
Jacob Hudobenko ◽  
Anthony Patrizz ◽  
Louise D McCullough
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
The Elderly ◽  
Vehicle Group ◽  
Peripheral Tissues ◽  
Delayed Treatment ◽  
Aged Mice ◽  
Infarct Area ◽  
Age Related

Introduction: GDF 11 is a member of the transforming growth factor β superfamily. Loss of GDF11 occurs with aging and declining levels correlate with several detrimental age-associated phenotypes in both peripheral tissues and brain. Restoration of GDF11 enhances neurogenesis and cognitive function in aged mice. Brain expression of GDF11 has not been investigated after stroke. Stroke differentially affects the elderly. In this work we examined the role of GDF11 in aging, stroke and its potential utility as a neuroprotective agent. Methods: Male C57/BL6NCrl young (2-3 months) and aged (19-21) mice were used. Brain GDF11 expression was evaluated in young and aged mice by western blot. Focal ischemia was induced with a transient middle cerebral artery occlusion (MCAO). Mice were randomly assigned into two groups and were subjected to 90 min MCAO. Group 1 received vehicle (phosphate buffered saline) and group 2 was administered rGDF11 (100 ug/kg., ip) at the onset of ischemia. In additional experiments, the efficacy of delayed treatment (3 h after ischemia) with rGDF11 was tested. These mice were subjected to a 60 min MCAO. Mice were euthanized after 24 hours and 7 days respectively and brains were harvested to estimate infarct area. Results: A significant decrease in brain GDF11 levels was observed in aged mice as compared to young (p<0.05). Additionally, a significant decline in brain GDF11 expression was observed after stroke at 24 hours vs. sham groups (p<0.05). A significant decrease in cortical and hemispheric infarct area was observed in the rGDF11 group (cortical 48.73±1.05; hemisphere 49.68±3.58) as compared to vehicle group (60.54±4.88; 61.35±6.03), when GDF was administered at the time of ischemia. Delayed treatment with rGDF11 also reduced infarct at 7 days. Conclusions: Brain GDF11 levels decline with age and after stroke. Supplementation with rGDF11 ameliorates stroke induced injury in young mice at 24h and 7 days. These finding suggest potential role of GDF11 in age and stroke. Restoration of age-related loss of GDF may be a viable therapy for stroke.

scholarly journals Subcutaneous neurotrophin-3 infusion induces corticospinal neuroplasticity and improvements in dexterity and walking in elderly rats after large cortical strokes

2018 ◽  
Author(s):  
Denise Duricki ◽  
Sotiris Kakanos ◽  
Barbara Haenzi ◽  
Wayman Christina ◽  
Diana Cash ◽  
...  
Keyword(s):  
Muscle Spindles ◽  
Time Frame ◽  
Sensory Function ◽  
Subcutaneous Infusion ◽  
Delayed Treatment ◽  
Neurotrophin 3 ◽  
Cortical Stroke ◽  
High Doses ◽  
And Function ◽  
Sensorimotor Recovery

AbstractThere is an urgent need for a therapy which reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. Neurotrophin-3 (NT3) is a growth factor made by muscle spindles and skin which is required for the survival, development and function of locomotor circuits involving afferents from muscle and skin that mediate proprioception and tactile sensation. We set out to determine whether subcutaneous supplementation of NT3 improves sensorimotor recovery after stroke in elderly rats. We show that one-month-long subcutaneous infusion of NT3 protein induces sensorimotor recovery after cortical stroke in elderly rats. Specifically, in a randomised, blinded pre-clinical trial, we show improved dexterity, walking and sensory function in rats following cortical ischemic stroke when treatment with NT3 is initiated 24 hours after stroke. Importantly, NT-3 was given in a clinically-feasible timeframe via this straightforward route. MRI and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, anterograde tracing showed that corticospinal axons from the less-affected hemisphere sprouted in the spinal cord from cervical levels 2 to 8. Importantly, Phase I and II clinical trials by others show that repeated, subcutaneously administered high doses of recombinant NT-3 are safe and well tolerated in humans with other conditions. This paves the way for NT-3 as a therapy for stroke.

scholarly journals Exploring How Low Oxygen Post Conditioning Improves Stroke-Induced Cognitive Impairment: A Consideration of Amyloid-Beta Loading and Other Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Zidan Zhao ◽  
Rebecca J. Hood ◽  
Lin Kooi Ong ◽  
Giovanni Pietrogrande ◽  
Sonia Sanchez Bezanilla ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Amyloid Beta ◽  
Neuronal Loss ◽  
Treatment Phase ◽  
Experimental Stroke ◽  
Low Oxygen ◽  
Associate Learning ◽  
Atmospheric Air ◽  
Post Stroke ◽  
Cognitive Benefits

Cognitive impairment is a common and disruptive outcome for stroke survivors, which is recognized to be notoriously difficult to treat. Previously, we have shown that low oxygen post-conditioning (LOPC) improves motor function and limits secondary neuronal loss in the thalamus after experimental stroke. There is also emerging evidence that LOPC may improve cognitive function post-stroke. In the current study we aimed to explore how exposure to LOPC may improve cognition post-stroke. Experimental stroke was induced using photothrombotic occlusion in adult, male C57BL/6 mice. At 72 h post-stroke animals were randomly assigned to either normal atmospheric air or to one of two low oxygen (11% O2) exposure groups (either 8 or 24 h/day for 14 days). Cognition was assessed during the treatment phase using a touchscreen based paired-associate learning assessment. At the end of treatment (17 days post-stroke) mice were euthanized and tissue was collected for subsequent histology and biochemical analysis. LOPC (both 8 and 24 h) enhanced learning and memory in the 2nd week post-stroke when compared with stroke animals exposed to atmospheric air. Additionally we observed LOPC was associated with lower levels of neuronal loss, the restoration of several vascular deficits, as well as a reduction in the severity of the amyloid-beta (Aβ) burden. These findings provide further insight into the pro-cognitive benefits of LOPC.

scholarly journals Remote Corticospinal Tract Degeneration After Cortical Stroke in Rats May Not Preclude Spontaneous Sensorimotor Recovery

2021 ◽  
pp. 154596832110413
Author(s):  
Michel R. T. Sinke ◽  
Geralda A. F. van Tilborg ◽  
Anu E. Meerwaldt ◽  
Caroline L. van Heijningen ◽  
Annette van der Toorn ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Corticospinal Tract ◽  
Sprague Dawley ◽  
Post Stroke ◽  
Neuronal Communication ◽  
Cortical Stroke ◽  
Magnetic Resonance Imaging Mri ◽  
And Behavior ◽  
Sensorimotor Recovery

Background. Recovery of motor function after stroke appears to be related to the integrity of axonal connections in the corticospinal tract (CST) and corpus callosum, which may both be affected after cortical stroke. Objective. In the present study, we aimed to elucidate the relationship of changes in measures of the CST and transcallosal tract integrity, with the interhemispheric functional connectivity and sensorimotor performance after experimental cortical stroke. Methods. We conducted in vivo diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and behavior testing in twenty-five male Sprague Dawley rats recovering from unilateral photothrombotic stroke in the sensorimotor cortex. Twenty-three healthy rats served as controls. Results. A reduction in the number of reconstructed fibers, a lower fractional anisotropy, and higher radial diffusivity in the ipsilesional but intact CST, reflected remote white matter degeneration. In contrast, transcallosal tract integrity remained preserved. Functional connectivity between the ipsi- and contralesional forelimb regions of the primary somatosensory cortex significantly reduced at week 8 post-stroke. Comparably, usage of the stroke-affected forelimb was normal at week 28, following significant initial impairment between day 1 and week 8 post-stroke. Conclusions. Our study shows that post-stroke motor recovery is possible despite degeneration in the CST and may be supported by intact neuronal communication between hemispheres.

Abstract TP78: Combination of Neuroprotective Drug and Neural Stem Cells Benefits Aged Stroke Mice with Delayed Tissue Plasminogen Activator Treatment

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Auston Eckert ◽  
Milton H Hamblin ◽  
Jean-Pyo Lee
Keyword(s):  
Stem Cells ◽  
Young Adult ◽  
Neural Stem Cells ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Inflammatory Drug ◽  
Aged Mice ◽  
Post Stroke ◽  
Adult Mice ◽  
Tissue Plasminogen

Background: Presently, tissue plasminogen activator (tPA) is the sole FDA-approved antithrombotic treatment available for stroke. However, tPA’s harmful side effects within the central nervous system can exacerbate blood-brain barrier (BBB) damage and increase mortality. Patients should receive tPA less than 4.5 hours post-stroke. Although age alone is not an impediment for tPA treatment, the harmful effects of delayed tPA (>4.5h), particularly on aged stroke animals, have not been well studied. We reported that intracranial transplantation of neural stem cells (hNSCs) ameliorates BBB damage caused by ischemic stroke. In this study, we examined the combined effects of minocycline (a neuroprotective and anti-inflammatory drug) and hNSC transplantation on the mortality of delayed tPA-treated aged mice within 48h post-stroke. Methods and Results: We utilized the middle cerebral artery occlusion stroke mouse model to induce focal cerebral ischemia followed by reperfusion (MCAO/R). 6h post-MCAO, we administered tPA intravenously. Minocycline was administered intraperitoneally at various time points prior to tPA injection. One day post-stroke, we injected hNSCs intracranially. Previously, we reported that hNSCs (both human and mouse) transplanted into the brain 24h post-stroke rapidly improve neurological outcome in young-adult mice (4-5mo). In our current study, tPA administered within 4.5h did not increase mortality in either young-adult or aged mice. However, we found delayed tPA treatment (6h post-stroke) significantly increased the mortality of aged mice (13-18 mo) but not in young-adult mice. Here, we report that by combining minocycline prior to tPA significantly reduced mortality. Furthermore, transplanting hNSCs in minocycline-treated mice further ameliorated the pathophysiology caused by delayed tPA. Conclusions: Our findings implicate that administering the anti-apototic and anti-inflammatory drug prior to tPA injection, and then post-treating with multipotent neuroprotective hNSCs might expand the time window of tPA and reduce reperfusion injury.

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