Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.
Background and Purpose-Lacunar infarction accounts for 25% of ischemic strokes, but the pathological characteristics have not been investigated systematically. A new experimental model of lacunar infarction in the miniature pig was developed to investigate the pathophysiological changes in the corticospinal tract from the acute to chronic phases. Methods-Thirty-five miniature pigs underwent transcranial surgery for permanent anterior choroidal artery occlusion.Animals recovered for 24 hours (nϭ7), 2 (nϭ5), 3 (nϭ2), 4 (nϭ2), 6 (nϭ1), 7 (nϭ7), 8 (nϭ2), and 9 days (nϭ1), 2 weeks (nϭ2), 4 weeks (nϭ3), and more than 4 weeks (nϭ3). Neurology, electrophysiology, histology, and MRI were performed. Seven additional miniature pigs underwent transient anterior choroidal artery occlusion to study muscle motor-evoked potentials and evaluate corticospinal tract function during transient anterior choroidal artery occlusion. Results-The protocol had a 91.4% success rate in induction of internal capsule infarction 286Ϯ153 mm 3 (meanϮSD). Motor-evoked potentials revealed the presence of penumbral tissue in the internal capsule after 6 to 15 minutes anterior choroidal artery occlusion. Total neurological deficit scores of 15.0 (95% CI, 13.5 to 16.4) and 3.4 (0.3 to 6.4) were recorded for permanent anterior choroidal artery occlusion and sham groups, respectively (PϽ0.001, maximum score 25) with motor deficit scores of 3.4 (95% CI, 2.9 to 4.0) and 0.0 (CI, 0.0 to 0.0), respectively (PϽ0.001, maximum score 9). Histology revealed that the internal capsule lesion expands gradually from acute to chronic phases. Conclusions-This
C erebral large vessel occlusion is a life-threatening disease and causes neurological disorders. In addition to early recanalization with intravenous tissue plasminogen alteplase injection, multiple randomized control trials have recently demonstrated the efficacy and safety of mechanical thrombectomy using a stent retriever.1-6 However, reactive oxygen species (ROS) generation increases during reperfusion, which impairs survival and aggravates neurological function because of secondary brain injury, including hemorrhage in the ischemic area and brain edema. The functional disability rate was 30% to 70% after mechanical thrombectomy, and symptomatic hemorrhagic complication rate was up to 10%. [1][2][3][4][5][6] Oxidative stress suppression after reperfusion is a potential therapeutic strategy and can improve survival and the functional prognosis. Nitroxide (NO) radicals are free radical scavengers with known neuroprotective functions against cerebral ischemia in rodent models.7-9 The 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) is a stable Background and Purpose-Reperfusion therapy by mechanical thrombectomy is used to treat acute ischemic stroke.However, reactive oxygen species generation after reperfusion therapy causes cerebral ischemia-reperfusion injury, which aggravates cerebral infarction. There is limited evidence for clinical efficacy in stroke for antioxidants. Here, we developed a novel core-shell type nanoparticle containing 4-amino-4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (nitroxide radical-containing nanoparticles [RNPs]) and investigated its ability to scavenge reactive oxygen species and confer neuroprotection. Methods-C57BL/6J mice underwent transient middle cerebral artery occlusion and then received RNPs (9 mg/kg) through the common carotid artery. Infarction size, neurological scale, and blood-brain barrier damage were visualized by Evans blue extravasation 24 hours after reperfusion. RNP distribution was detected by rhodamine labeling. Blood-brain barrier damage, neuronal apoptosis, and oxidative neuronal cell damage were evaluated in ischemic brains. Multiple free radicalscavenging capacities were analyzed by an electron paramagnetic resonance-based method. Results-RNPs were detected in endothelial cells and around neuronal cells in the ischemic lesion. Infarction size, neurological scale, and Evans blue extravasation were significantly lower after RNP treatment. RNP treatment preserved the endothelium and endothelial tight junctions in the ischemic brain; neuronal apoptosis, O 2 − production, and gene oxidation were significantly suppressed. Reactive oxygen species scavenging capacities against OH, ROO, and O 2 − improved by RNP treatment. Conclusions-An intra-arterial RNP injection after cerebral ischemia-reperfusion injury reduced blood-brain barrier damage and infarction volume by improving multiple reactive oxygen species scavenging capacities. Therefore, RNPs can provide neurovascular unit protection. Visual Overview-An online visual overview is available for this a...
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