Rodent Models of Post-Stroke Dementia

Post-stroke cognitive impairment is one of the most common complications in stroke survivors. Concomitant vascular risk factors, including aging, diabetes mellitus, hypertension, dyslipidemia, or underlying pathologic conditions, such as chronic cerebral hypoperfusion, white matter hyperintensities, or Alzheimer’s disease pathology, can predispose patients to develop post-stroke dementia (PSD). Given the various clinical conditions associated with PSD, a single animal model for PSD is not possible. Animal models of PSD that consider these diverse clinical situations have not been well-studied. In this literature review, diverse rodent models that simulate the various clinical conditions of PSD have been evaluated. Heterogeneous rodent models of PSD are classified into the following categories: surgical technique, special structure, and comorbid condition. The characteristics of individual models and their clinical significance are discussed in detail. Diverse rodent models mimicking the specific pathomechanisms of PSD could provide effective animal platforms for future studies investigating the characteristics and pathophysiology of PSD

Effects of Fructus mume Extract on MAPK and NF-κB Signaling and the Resultant Improvement in the Cognitive Deficits Induced by Chronic Cerebral Hypoperfusion

Fructus mume (F. mume) has been used as a medicinal food in Japan and has been reported to have anti-inflammatory effects in inflammatory bowel disease and macrophage-mediated inflammation. We investigated the effects of F. mume extracts on cognitive dysfunction in rats with chronic cerebral hypoperfusion and the molecular mechanisms underlying these effects. Chronic cerebral hypoperfusion was induced in male Wister rats by bilateral common artery occlusion (BCCAo). Daily administration of F. mume extracts was started on day 20 after post-BCCAo and continued for 40 days. The status of hippocampus-dependent memory was evaluated in control rats, rats with chronic cerebral hypoperfusion, and rats with chronic cerebral hypoperfusion that were administered F. mume. The levels of microglial activation were measured in the hippocampus and the fimbria of hippocampus, and expression levels of hippocampal mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were examined. Rats that received chronic cerebral hypoperfusion showed spatial memory impairments relative to the control rats; these impairments were reduced by daily administration of F. mume. Administration of F. mume mitigated the microglial activation and alterations of hippocampal MAPK and NF-κB signaling in the rats with chronic cerebral hypoperfusion. These results indicate that F. mume may possess therapeutic potential for the prevention of vascular dementia via inhibition of inflammatory processes

Characterization of Tauopathy in a Rat Model of Post-Stroke Dementia Combining Acute Infarct and Chronic Cerebral Hypoperfusion

Post-stroke dementia (PSD) is a major neurodegenerative consequence of stroke. Tauopathy has been reported in diverse neurodegenerative diseases. We investigated the cognitive impairment and pathomechanism associated with tauopathy in a rat model of PSD by modeling acute ischemic stroke and underlying chronic cerebral hypoperfusion (CCH). We performed middle cerebral artery occlusion (MCAO) surgery in rats to mimic acute ischemic stroke, followed by bilateral common carotid artery occlusion (BCCAo) surgery to mimic CCH. We performed behavioral tests and focused on the characterization of tauopathy through histology. Parenchymal infiltration of cerebrospinal fluid (CSF) tracers after intracisternal injection was examined to evaluate glymphatic function. In an animal model of PSD, cognitive impairment was aggravated when BCCAo was combined with MCAO. Tauopathy, manifested by tau hyperphosphorylation, was prominent in the peri-infarct area when CCH was combined. Synergistic accentuation of tauopathy was evident in the white matter. Microtubules in the neuronal axon and myelin sheath showed partial colocalization with the hyperphosphorylated tau, whereas oligodendrocytes showed near-complete colocalization. Parenchymal infiltration of CSF tracers was attenuated in the PSD model. Our experimental results suggest a hypothesis that CCH may aggravate cognitive impairment and tau hyperphosphorylation in a rat model of PSD by interfering with tau clearance through the glymphatic system. Therapeutic strategies to improve the clearance of brain metabolic wastes, including tau, may be a promising approach to prevent PSD after stroke

Swiprosin-1 dimerizes through its coiled-coil domain, and calcium ions are required for the dimer conformation.

<p>(A) HEK293T cells (2×10⁶) were transiently transfected with 4 µg of GFP, GFP_Swip-1, and myc or increasing concentrations (4, 7, and 11 µg) of myc_Swip-1. The cell lysates were immunoprecipitated with anti-GFP-conjugated beads. Immune complexes were resolved on by SDS-PAGE and blotted with anti-GFP or anti-myc antibodies. (B) HEK293T cells (2×10⁶) were transiently transfected with GFP, GFP_Swip-1, or mutant GFP_SW1s (M1, M2, and M3). The cell lysates were incubated on ice with glutaraldehyde (GA) at the indicated concentrations (0.001–0.01%) for 20 min. The samples were resolved on SDS-PAGE and blotted with anti-GFP antibodies. The positions of monomer (M), dimer (D), tetramer (T), and GFP alone (G) are indicated by arrows. (C) The purified wild-type His_Swip-1 or wild-type GST_Swip-1 (a) and coiled-coil domain deletion mutants (l, m, and n) were co-incubated with glutathione (GSH)-Sepharose 4B beads for 2 h at 4°C, and the samples were then resolved by SDS-PAGE and blotted with anti-His antibodies (left). Each sample was compared to a loading control (right). (D) The cells from (A) were incubated for 1 h with 20 µM BAPT-AM or 2 µM ionomycin. The cell lysates were immunoprecipitated in the presence of 2 mM EGTA (BAPTA-treated cells) or 1 mM CaCl2 (ionomycin-treated cells), and the amount of binding protein as well as the expression of the indicated proteins were then evaluated by western blotting. All the procedures were performed in the presence of 10 µM cytochalasin D to exclude the effect of actin polymerization. (E) The purified wild-type His_Swip-1 and wild-type GST_Swip-1 (a) or coiled-coil domain containing mutants (h, i) were co-incubated with glutathione (GSH)-Sepharose 4B beads for 2 h at 4°C in the presence or absence of 2 mM EGTA, and the samples were then resolved by SDS-PAGE and blotted with anti-His antibodies (left). Each sample was compared to a loading control (right).</p

Swiprosin-1 induces actin bundling in vitro.

<p>(A) F-actin (2 µM) was incubated with various concentrations of His_Swip-1 (0.25–4 µM) for 30 min. The samples were assessed for actin-bundling activity as described in the Experimental Procedures. The percentage of total actin in the pellet was quantified (bottom). S, supernatant; P, pellet. (B and C) Electron micrographs of actin filaments (2 µM) after incubation with or without His_Swip-1 (4 µM) (B) or GST_Swip-1 (4 µM) (C).</p