Focal Cerebral Infarction Research Articles

High prevalence of neonatal presentation in Korean patients with citrullinemia type 1, and their shared mutations

Type 1 citrullinemia (CTLN1) often presents as a hyperammonemic encephalopathy in the neonatal period, but it can also develop in the late-infantile period and in adults. In addition, some patients can be identified in the presymptomatic period by neonatal or family member screening. In this study, twenty Korean patients with CTLN1 (19 families) were examined; fourteen patients with neonatal-onset, three with late-onset, and three that were identified presymptomatically. The 13 patients with hyperammonemic encephalopathy received continuous venovenous hemofiltration (CVVH) or peritoneal dialysis (PD). Although the hyperammonemia was relieved more effectively in the six patients on CVVH than the seven on PD, most of these patients suffered from severe neurologic deficits. Recurrent hyperammonemic episodes (7 pts, 35%), recurrent and reversible acute hepatic dysfunction (5 pts, 25%), and focal cerebral infarction (2 pts, 10%) were noted. The neonates with hyperammonemic encephalopathy had extensive brain injuries at the onset of hyperammonemia, followed by encephalomalacia and brain atrophy at quite an early age. Genetic testing for the ASS1 gene revealed a different mutation spectrum from those of other ethnicities; Three common mutations, c.421-2A>G (37.8%), c.1128-6_1188dup67 (18.9%), and p.Gly324Ser (16.2%), accounted for 73% of the mutations. The poor outcome was expected in patients with the peak ammonia level at onset over 600μmol/L, whose proportion was higher in the neonatal presentation group than in the presymptomatic/late presentation group. Our findings add to the current understanding of the ethnic diversity of CTLN1 from both clinical and genetic perspectives.

Localizing coordinates of cerebral ischemic tissue without the need of staining in a rat model of focal cerebral infarct

Biochemical and metabolic analysis of ischemic cerebral tissue is central in stroke investigation and is usually performed in animal stroke models, such as the permanent occlusion of the middle cerebral artery (MCAO) in the rat that we have used. To be sure that the sample is from infarct tissue, it is differentiated from the surrounding normal tissue by staining, usually with 2,3,5-triphenyltetrazolium chloride (TTC), but staining can hamper biochemical colorimetric analysis. We performed this study to avoid this obstacle. A cerebral infarct was provoked in a sample of 10 rats and the brain was cut in coronal sections that were stained with TTC so that the unstained, infarct areas could be delineated in a template of each section in which areas with infarct in all animals were delineated. We calculated infarct coordinates and depth so that the infarct tissue can be sampled without staining. For more precision, the ischemic cortex can be delimited staining its surface before sectioning and cortical tissue into which TTC diffuses can be afterwards discarded, as we had previously measured the TTC diffusion depth in rat brains.

Influence of constraint‐induced movement therapy upon evoked potentials in rats with cerebral infarction

Constraint-induced movement therapy (CIMT) is an effective treatment promoting motor recovery of upper extremity function in stroke patients. The objective of the present study was to determine the effect of CIMT on the evoked potentials in rats with focal cerebral cortical ischemia induced by endothelin-1 (ET-1). Thirty rats were randomly assigned to the sham, infarct or CIMT groups. ET-1 was injected stereotaxically into the forelimb area of the cerebral cortex in the dominant hemisphere. Custom-made constraint jackets were applied to limit movement of the unaffected forelimb in the CIMT group. Motor and sensory function of the forelimb was evaluated by a pellet retrieval task and forearm asymmetry test. Electrophysiologic changes were evaluated by motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SEPs). The location and extent of cerebral ischemia were confirmed and compared histologically. The CIMT group showed better recovery in the pellet retrieval task. Forelimb use was more symmetrical in the CIMT group. The waveform of the SEP was reversed and delayed in the infarct group, but it was preserved in the CIMT group with amplitude decrease only. The estimated volume of infarction was smaller in the CIMT group, although statistically not significant. The results demonstrate that CIMT can promote recovery of motor function in focal cerebral cortical infarcts, and that recovery may be related to reorganization of the cerebral neuronal network in the somatosensory pathway.

Letter by Hiltunen and Jolkkonen Regarding Article, “Secondary Neurodegeneration in Remote Regions After Focal Cerebral Infarction: A New Target for Stroke Management?”

To the Editor: We read with interest the recent article by Zhang et al.1 The authors described secondary degeneration in remote regions after experimental cerebral ischemia, which could provide a target for stroke management. We completely agree that this is an appealing approach. However, the underlying pathology may be different in ischemic rodents and patients with stroke. Remote areas such as the thalamus connected to the cortical infarct are affected because of delayed retrograde degeneration of afferent connections. This is associated with extensive and complex pathology including inflammatory reactions, β-amyloid (Aβ) accumulation, calcification, and angiogenesis in rats subjected to middle …

Therapeutic effect of nerve growth factor on cerebral infarction in dogs using the hemisphere anomalous volume ratio of diffusion-weighted magnetic resonance imaging.

A model of focal cerebral ischemic infarction was established in dogs through middle cerebral artery occlusion of the right side. Thirty minutes after occlusion, models were injected with nerve growth factor adjacent to the infarct locus. The therapeutic effect of nerve growth factor against cerebral infarction was assessed using the hemisphere anomalous volume ratio, a quantitative index of diffusion-weighted MRI. At 6 hours, 24 hours, 7 days and 3 months after modeling, the hemisphere anomalous volume ratio was significantly reduced after treatment with nerve growth factor. Hematoxylin-eosin staining, immunohistochemistry, electron microscopy and neurological function scores showed that infarct defects were slightly reduced and neurological function significantly improved after nerve growth factor treatment. This result was consistent with diffusion-weighted MRI measurements. Experimental findings indicate that nerve growth factor can protect against cerebral infarction, and that the hemisphere anomalous volume ratio of diffusion-weighted MRI can be used to evaluate the therapeutic effect.

Response to Letter Regarding Article, “Secondary Neurodegeneration in Remote Regions After Focal Cerebral Infarction: A New Target for Stroke Management?”

Response: We thank Drs Hiltunen and Jolkkonen for their interest in our article regarding secondary neurodegeneration after focal cerebral infarction and their thoughtful comments.1 Focal cerebral infarction after middle cerebral artery occlusion not only causes neuronal damage in the area of ischemia, but also leads to secondary neuronal death and glial reaction in remote regions, including the ipsilateral thalamus, substantia nigra, and distal pyramidal tract.1 Retrograde degeneration of the thalamocortical fibers is believed to contribute to secondary neurodegeneration in …

Effects of exercise after focal cerebral cortex infarction on basal ganglion

Identification of functional molecules in the brain related to improvement of motor dysfunction after stroke will contribute to establish a new treatment strategy for stroke rehabilitation. Hence, monoamine changes in basal ganglion related to motor control were examined in groups with/without voluntary exercise after cerebral infarction. Cerebral infarction was produced by photothrombosis in rats. Voluntary exercise using a running wheel was initiated from 2 days after surgery. Motor performance was measured by the accelerated rotarod test. Monoamine concentrations in striatum were analyzed using HPLC and immunohistochemical staining performed with anti-tyrosine hydroxylase antibody. In behavioral evaluation, the mean latency until falling from the rotating rod in the group with exercise (infarction-EX group) was significantly longer than that in the group without exercise (infarction-CNT group). When concerning the alteration of monoamine concentration between before and 2 days after infarction, dopamine level showed a significant increase 2 days after infarction. Subsequently, dopamine level was significantly decreased in the infarction-EX group at 10 days after infarction; in contrast, both norepinephrine and 5-HT concentrations were significantly higher in the infarction-EX group than in the infarction-CNT group. Furthermore, duration of rotarod test showed a significant inverse correlation with dopamine levels and a significant positive correlation with 5-HT levels. In immunohistochemical analysis, tyrosine hydroxylase immunoreactivity in substantia nigra pars compacta was shown to increase in the infarction-CNT group. In the present study, at least some of the alterations of monoamines associated with the improvement of paralysis in the basal ganglion related to motor control might have been detected.

NG2 and NG2‐positive cells delineate focal cerebral infarct demarcation in rats

Focal cerebral ischemia induces cellular responses that may result in secondary tissue damage. We recently demonstrated multi-facetted spatial and temporal patterns of neuroinflammation by multimodal imaging. In the present study, we especially focus on the separation of vital and necrotic tissue, which enabled us to define a demarcation zone. Focal cerebral ischemia was induced via macrosphere embolization of the middle cerebral artery in Wistar rats. Subsequent cellular processes were investigated immunohistochemically from 3 to 56 days after onset of ischemia. We detected several infarct subareas: a necrotic infarct core and its margin adjacent to a nerve/glial antigen 2 (NG2)+ zone delineating it from a vital peri-infarct zone. Initially transition from necrotic to vital tissue was gradual; later on necrosis was precisely separated from vital tissue by a narrow NG2+ belt that was devoid of astrocytes, oligodendrocytes or neurons. Within this demarcation zone NG2+ cells associate with ionized calcium binding adaptor molecule 1 (Iba1) but not with GFAP, neuronal nuclear antigen (NeuN) or 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase). During further infarct maturation NG2 seemed to be positioned in the extracellular matrix (ECM) of the demarcation zone, whereas Iba1+ cells invaded the necrotic infarct core and GFAP+ cells built a gliotic containing belt between the lesion and NeuN+ unaffected tissue. Overall, our data suggested that NG2 proteoglycan expression and secretion hallmarked demarcation as a process that actively separated necrosis from vital tissue and therefore decisively impacts secondary neurodegeneration after ischemic stroke.

Discrete progression of migraine-induced focal cerebral infarction

Migraine-induced infarction is rare and possibly overdiagnosed [1]. Although the relationship between migraine and stroke has historically been a subject of controversy, recent evidence has lent support to the notion that migraine and stroke are co-morbid conditions linked by complex pathophysiological processes [2]. Migraine with aura is more clearly associated with increased stroke risk than is common migraine, with studies implicating smoking [3] and elevated plasma homocysteine [4], among a host of factors, as mediating risk. There appears to be a predilection for stroke localization within the posterior cerebral artery (PCA) territory [5]. The patient reported herein represents an example of migraine-induced infarction. A 66-year-old man with a history adolescent-onset classic migraine presented with prolongation of his typical symptoms, consisting of scintillating scotoma in the right visual field, followed by perioral parethesia, mild dysarthria, and anomic aphasia, and concluding with relatively mild occipital headache. Typical frequency was one to four episodes monthly with a duration of 3–4 h each. In contrast, the duration of the presenting episode was protracted, lasting between 48 and 72 h. Symptoms responded briskly to solumedrol 125 mg IV and subcutaneous sumatriptan 6 mg. The patient reported one other life-time episode suggesting migraine status several years previously with no residual symptoms. The neurological examination was unremarkable; subjectively, however, the patient reported persisting visual scotoma located 10 –15 to the right of foveation. Since the event, he also complained of increased forgetfulness requiring the use of compensatory lists and which contributed to his decision to delegate responsibility for managing the family finances to his spouse. Neuropsychological evaluation revealed deficits in memory for verbal material and confrontation naming; his MMSE score was 27/30. MRI with contrast revealed a focal gyral pattern of signal hyperintensity on T1-, T2-weighted, and FLAIR sequences, with associated heterogeneous enhancement consistent with laminar necrosis from evolving subacute to chronic infarction in the left PCA distribution, affecting the mesial occipital region. Scattered, punctate areas of T2 and FLAIR hyperintensity were also noted in subcortical white matter (Fig. 1). Mass lesion, vascular malformation, and focal cerebritis were excluded. EEG obtained 2 years prior to that event was normal, effectively ruling out seizure disorder. Carotid Doppler study showed mild stenosis (16–49 %) of the internal carotid arteries bilaterally. Pertinent laboratory studies including ESR (10) and CRP (0.411) were normal, but homocysteine was elevated (15.1). TSH, vitamin B12, folate, and RPR were unremarkable. Migraine status with characteristic aura recurred 21 months later. Neurological examination following that event was remarkable only for a homonymous right superior quandrantanopia. Follow-up neuropsychological evaluation showed interval decline in memory, speed of visual search, cognitive flexibility, problem solving, and S. P. Cercy (&) Department of Psychiatry, New York University School of Medicine, 423 E 23rd Street, New York, NY 10010, USA e-mail: Steven.Cercy@va.gov

Secondary Neurodegeneration in Remote Regions After Focal Cerebral Infarction

Cerebral infarction-induced cessation of function in areas of the brain remote from, but connected to, the primary site of damage was termed “diaschisis” by von Monakow.1 Initially, the concept of diaschisis did not include morphological changes. However, accumulating evidence has shown that histopathologic changes also occur in nonischemic remote brain regions that have synaptic connections with the primary lesion site. For example, after cerebral infarction in the middle cerebral artery (MCA) territory, neuronal death, gliosis, and axonal degeneration have been found in the ipsilateral thalamus, substantia nigra (SN), and distal pyramidal tract, all of which lie outside the MCA territory.2–7 This kind of secondary neurodegeneration occurs selectively in such areas several days or weeks after stroke onset, and this can be detected by neuroimaging techniques.8 For quite a long time, the role of secondary degeneration in stroke recovery has not been well understood. Recently, emerging studies suggest that secondary degeneration is associated with neurological deficits and can predict motor outcome after stroke.9–15 In this review, we aimed to summarize the pathological and neuroimaging evidence of secondary neurodegeneration in the ipsilateral thalamus, SN, and pyramidal tract after MCA infarction and described its potential significance for stroke management. We searched PubMed from 1980 to September 2011, using the terms “cerebral infarction,” “middle cerebral artery,” “Wallerian degeneration,” “anterograde degeneration,” “retrograde degeneration,” and “transneuronal degeneration.” Further articles were identified from the references cited in those articles and through searches of our personal files. The final list of references was selected on the basis of originality and relevance to the topics covered in this review. ### Postmortem Studies Data from postmortem studies provide direct evidence of secondary neurodegeneration after focal cerebral infarction (Figure 1). Histopathologic examination at 4 months after MCA infarction revealed a delayed and selective decrease in the …

Effects of exercise training on synaptic plasticity in rats with focal cerebral infarction

To examine the roles of exercise training in the improvement of damaged neural function and synaptic plasticity. An infarction model was induced by left middle cerebral artery occlusion (MCAO). A total of 70 adult Sprague-Dawley rats were randomly divided into 3 groups: physical exercise group (n = 30) undergoing running wheel exercise daily after MCAO, control group (n = 30) and sham-operated group (n = 10). The latter two groups were fed in standard cages without any special training exercise. The rats were scarified at Days 3, 7, 14, 21 and 35 for the evaluation of neural function by neurological severity scores (NSS). And the synaptic ultrastructures at peri-infarction region were examined by specific marker synaptophysin (SYN). Synaptic ultrastructures at peri-infarction region were observed in both the control and exercise training groups. The presynaptic and postsynaptic membranes were relatively intact. And the presynaptic membranes had more synaptic vesicles from Day 7 post-ischemia. The number of SYN positive cells significantly increased in the exercise training group (21 d: 0.8 ± 0.1; 35 d: 0.7 ± 0.1) versus those in the control group (21 d: 0.4 ± 0.1; 35 d: 0.5 ± 0.1) at Days 21 and 35 post-ischemia (P < 0.05). Moreover, the neurological severity scores in the exercise training group (7 d: 7.8 ± 0.8; 14 d: 5.6 ± 0.8; 21 d: 3.3 ± 0.8; 35 d: 3.0 ± 0.8) showed a quicker declination versus those in the control group (7 d: 8.8 ± 0.7; 14 d: 7.7 ± 0.9; 21 d: 6.9 ± 0.8; 35 d: 4.2 ± 0.8) from Day 7 post-ischemia (P < 0.05). Exercise training plays an important role in the recovery of damaged neural function and synaptic plasticity after cerebral infarction in rats.

Effects of different frequencies of electro-acupuncture at Shuigou (GV 26) on recovery of motor function in rats with focal cerebral ischemic injury

ObjectiveTo investigate the effects of different frequencies of electro-acupuncture at Shuigou (GV 26) on the latent period and wave amplitude of motor evoked potentials (MEPs) in rats with focal cerebral infarction. MethodsFifty healthy male Wistar rats were randomly divided into five groups: controls, model, 2 Hz Shuigou, 50 Hz Shuigou and 100 Hz Shuigou. There were 10 rats in each group. Using a modification of a technique for middle cerebral artery occlusion, focal cerebral ischemic injury was induced in all rats except those in the control group. The rats in the control group received no treatment. After behavioral deficit had been evaluated using the Zausinger 6-point neurological function score, the rats in the Shuigou groups underwent acupuncture and continuous wave stimulation at a frequency of 2 Hz, 50 Hz or 100 Hz (intensity 1 mA) for 10 min twice daily for 3 days. The control and model groups underwent no intervention. Zausinger 6-point neurological function score and MEPs were measured 72 h after the start of treatment. ResultsThe neurological function scores of the three Shuigou groups were significantly higher than those of the model group (P<0.05). There was no significant difference between sides in the latency and amplitude of MEPs in the model group (P>0.05). The latency on the affected side in the model group was significantly longer than that in the control group (P<0.05) and the amplitude on affected side was significantly reduced (P<0.01). After 3 days of electro-acupuncture, the latency on the affected side in the 2 Hz Shuigou group was significantly shortened (P<0.05) and the amplitude was significantly increased (P<0.05) compared with the model group. ConclusionLow frequency electro-acupuncture at Shuigou (GV 26) can promote recovery of motor function after focal cerebral ischemic injury in rats.

Changing Pattern of Perinatal Brain Injury in Term Infants in Recent Years

Perinatal brain injury in term infants remains a significant clinical problem. Recently a change appears to have occurred in the pattern of such injuries. We sought to characterize the incidence, etiology, clinical manifestations, and outcomes of these injuries. A retrospective chart review identified clinical characteristics of neuroimaging, electroencephalography, and placental pathologic findings. Perinatal depression was defined as hypotonia and the need for respiratory support. From January 2004-December 2009, 29,597 term deliveries occurred. Brain injuries in 33 infants (live term births) included hypoxic-ischemic encephalopathy (n = 8; 0.27/1000), subdural hemorrhage (n = 10; 0.34/1000), intraventricular/intraparenchymal hemorrhage (n = 5; 0.17/1000), and focal cerebral infarctions (n = 4; 0.14/1000). Thirteen of 33 infants (39%) were triaged to a regular nursery. Delayed presentations included apnea (n = 6), desaturation episodes (n = 3), and seizures (n = 4). Twenty of 33 (61%) were admitted directly to the neonatal intensive care unit because of perinatal depression or evolving hypoxic-ischemic encephalopathy. Clinical signs included seizures (n = 12) and apnea (n = 2). Nine of 19 manifested electroencephalographic seizures. Pathology included chorioamnionitis (n = 7) and fetal thrombotic vasculopathy (n = 5). The latter was associated with focal cerebral infarctions in 3/4 cases. Most cases attributable to perinatal brain injury, except for evolving hypoxic-ischemic encephalopathy, are not identified according to any perinatal characteristics until the onset of signs, limiting opportunities for prevention.

Beclin 1 knockdown inhibits autophagic activation and prevents the secondary neurodegenerative damage in the ipsilateral thalamus following focal cerebral infarction

Cerebral infarction can cause secondary degeneration of thalamus and delay functional recovery. However, the mechanisms underlying secondary degeneration are unclear. The present study aimed to determine the occurrence and contribution of autophagy to the thalamic degeneration after cerebral infarction. Focal cerebral infarction was induced by distal middle cerebral artery occlusion (MCAO). Autophagic activation, Beclin 1 expression and amyloid β (Aβ) deposits were determined by immunofluorescence, immunoblot and electron microscopy. Secondary damage to thalamus was assessed with Nissl staining and immunofluorescence analysis. Apoptosis was determined using TUNEL staining. The contribution of autophagy to the secondary damage was evaluated by shRNA-mediated downregulation of Beclin 1 and the autophagic inhibitor, 3-methyladenine (3-MA). The potential role of Aβ in autophagic activation was determined with N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). The results showed that the conversion of LC3-II, the formation of autophagosomes, and the levels of activated cathepsin B and Beclin 1 were significantly increased in the ipsilateral thalamus at 7 and 14 days after MCAO (p < 0.05 or 0.01). Both Beclin 1 knockdown and 3-MA treatment significantly reduced LC3-II conversion and autophagosome formation, which were accompanied by obvious decreases in neuronal loss, gliosis and apoptosis in the ipsilateral thalamus (p < 0.05 or 0.01). Additionally, DAPT treatment markedly reduced Aβ deposits, which coincided with decreases in LC3-II conversion and autophagosome formation (p < 0.01). These results suggest that inhibition of autophagy by Beclin 1 knockdown can attenuate the secondary thalamic damage after focal cerebral infarction. Furthermore, Aβ deposits may be involved in the activation of autophagy.

The Effect of Combined Therapy of Exercise and Nootropic Agent on Cognitive Function in Focal Cerebral Infarction Rat Model

ObjectiveTo investigate the effect of combined therapy of exercise and nootropic agent on cognitive function in a focal cerebral infarction rat model.MethodForty 10-week old male Sprague-Dawley rats were subjected to photothrombotic cerebral infarction of the left parietal lobe. All rats were randomly divided into 4 groups: group A was photothrombotic cerebral infarction rats without any treatment (n=10); group B was photothrombotic cerebral infarction rats with swimming exercise (n=10); group C was photothrombotic cerebral infarction rats with oral administration of acetyl-L-carnitine (n=10); group D was photothrombotic cerebral infarction rats with swimming exercise and oral administration of acetyl-L-carnitine (n=10). Cognitive function was evaluated using the Morris water maze test on the 1st day, and the 1st, 2nd, and 4th week after the induction of cerebral infarction. The activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) in the hippocampus were measured. The neuronal cells of the hippocampus were histopathologically evaluated.ResultsThe escape latency was shorter in groups B, C, and D than in group A. However, the differences were not statistically significant at the 1st, 2nd and 4th week. The activity of SOD was the highest in group D. The level of MDA was the lowest in group D. We observed more normal neuronal cells in groups B, C, and D.ConclusionThe combined therapy of exercise and nootropic agent was helpful in ameliorating oxidative stress in the focal cerebral infarction rat model. However, the effect did not translate into improvement of cognitive function.

Predisposing factors, diagnosis, treatment and prognosis of cerebral venous thrombosis during pregnancy and postpartum: a case-control study.

Previous investigations have demonstrated a relatively low incidence of stroke among young women, though both pregnancy and delivery can substantially increase the risk. Cerebral venous thrombosis may manifest different characteristics during pregnancy and postpartum as a result of their specific physiological statuses. This study aimed to identify the clinical manifestations, diagnosis, treatment, and prognosis of cerebral venous thrombosis during pregnancy and postpartum. We conducted a retrospective analysis of 22 patients with cerebral venous thrombosis who were assigned to either group A (during pregnancy) or group B (during postpartum). The relevant risk factors, initiation and development of the disease, clinical presentations, diagnosis, treatment, and prognosis were compared between the two stages. Cerebral venous thrombosis occurred during both pregnancy and postpartum, but was more common postpartum. Patients in group A had a longer hospitalization period than those in group B. Confirmed predisposing factors in 85.7% of patients of group A were dehydration, infection, and underlying cerebrovascular disorders. No obvious predisposing factors were identified in group B. The most frequent symptom was headache, with epileptic seizures, hemiparalysis and aphasia being less frequent symptoms. Focal neurological symptoms (P = 0.022) and cerebral infarction (P = 0.014) occurred more frequently in group A than in group B. Anticoagulation therapy proved to be safe for cerebral venous thrombosis patients during puerperium, regardless of parenchymal hemorrhage. However, more attention should be paid to spontaneous in-site placental hemorrhage in pregnant patients. Both groups had similar prognoses (P = 1.000), with 36.3% patients suffering from consequential dysfunction or recurrent intracranial hypertension. Delayed diagnosis was associated with a poorer prognosis. Cerebral venous thrombosis manifests different clinical characteristics during pregnancy and postpartum, though both have a good prognosis. Early diagnosis and prompt anticoagulation therapy are essential.

Autophagosomes accumulation is associated with β‐amyloid deposits and secondary damage in the thalamus after focal cortical infarction in hypertensive rats

Focal cerebral cortical infarction after distal middle cerebral artery occlusion causes β-amyloid deposition and secondary neuronal degeneration in the ipsilateral ventroposterior nucleus of the thalamus. Several studies suggest that autophagy is an active pathway for β-amyloid peptide generation. This study aimed to investigate the role of autophagy in thalamic β-amyloid deposition and neuronal degeneration after cerebral cortical infarction in hypertensive rats. At 7 and 14days after middle cerebral artery occlusion, neuronal death and β-amyloid deposits were evident in the ipsilateral ventroposterior nucleus, and the activity of β-site amyloid precursor protein (APP)-cleaving enzyme 1, required for β-amyloid peptide generation, was elevated in the thalamus. In correlation, both the number of cells showing punctate microtubule-associated protein 1A light chain 3 fluorescence and levels of light chain 3-II protein, an autophagosome marker, were markedly increased. Notably, most of the cells that over-expressed β-site APP-cleaving enzyme 1 displayed punctate light chain 3 staining. Furthermore, the inhibition of autophagy with 3-methyladenine significantly reduced the thalamic neuronal damage, β-amyloid deposits, and β-site APP-cleaving enzyme 1 activity. These results suggest that autophagosomes accumulate within thalamic cells after cerebral cortical infarction, which is associated with thalamic β-amyloid deposition and secondary neuronal degeneration via elevation of β-site APP-cleaving enzyme 1 level.

Repeated administration of exendin-4 reduces focal cerebral ischemia-induced infarction in rats

Exendin-4 is a GLP-1 agonist that is clinically used for the treatment of diabetes mellitus and may also have neuroprotective effect. We explored the effect of repeated administration of exendin-4 (0.5 μg/kg, intraperitoneal twice a day for 7 days) on infarct volume, neurological deficit (neurological score, grip test, foot fault and rota rod tests), oxidative stress parameters (malondialdehyde, reduced glutathione, and superoxide dismutase) and expression of endothelin (ET) ET A and ET B receptors following cerebral ischemia produced in rats by permanent middle cerebral artery occlusion (MCAO). Since ET A receptors in the central nervous system (CNS) are involved in cerebral ischemia, we determined the effect of a specific ET A receptor antagonist, BQ123 (1 mg/kg, intravenously administered thrice: 30 min, 2 h and 4 h after MCAO for a total dose of 3 mg/kg) on cerebral ischemia in control and exendin-4 treated rats. Results indicate that exendin-4 treated rats had significant protection following MCAO induced cerebral ischemia. The infarct volume was 27% less compared to vehicle treated rats. The neurological deficit following MCAO was lower and oxidative stress parameters were improved in exendin-4 treated rats compared to control. BQ123 significantly improved infarct volume, oxidative stress parameters and neurological deficit in ischemic rats treated with vehicle or exendin-4. BQ123 induced protection from cerebral ischemia was similar in vehicle or exendin-4 treated rats. Expression of ET A receptors was significantly increased following cerebral ischemia which was not affected by exendin-4 treatment or by BQ123 administration. No change in expression of ET B receptors was observed following cerebral ischemia or any treatment. It is concluded that exendin-4 protects the CNS from damage due to cerebral ischemia by reducing oxidative stress and is independent of ET receptor involvement.

Chondroitin sulfate proteoglycans dephosphorylate TrkB and repress the synaptic plasticity

Focal cerebral infarction causes secondary damage in the ipsilateral ventroposterior thalamic nucleus (VPN). Chondroitin sulfate proteoglycans (CSPGs) are a family of putative inhibitory components, and its degradation by chondroitinase ABC (ChABC) promotes post-injury neurogenesis. This study investigated the role of ChABC in the primary and secondary injury post stroke in hypertension. Renovascular hypertensive Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO), and were subjected to continuous intra-infarct infusion of ChABC (0.12 U/d for 7 days) 24 h later. Neurological function was evaluated by a modified neurologic severity score. Neurons were counted in the peri-infarct region and the ipsilateral VPN 8 and 14 days after MCAO by Nissl staining and NeuN labeling. The expressions of CSPGs, growth-associated protein-43 (GAP-43) and synaptophysin (SYN) were detected with immunofluorescence or Western blotting. The intra-infarct infusion of ChABC, by degrading accumulated CSPGs, rescued neuronal loss and increased the levels of GAP-43 and SYN in both the ipsilateral cortex and VPN, indicating enhancd neuron survival as well as augmented axonal growth and synaptic plasticity, eventually improving overall neurological function. The study demonstrated that intra-infarct ChABC infusion could salvage the brain from both primary and secondary injury by the intervention on the neuroinhibitory environment post focal cerebral infarction.

Mechanism of neuronal circuit remodeling in contralateral hemisphere after focal cerebral infarction

Mechanism of neuronal circuit remodeling in contralateral hemisphere after focal cerebral infarction