Cortical spreading depolarization increases adult neurogenesis, and alters behavior and hippocampus-dependent memory in mice

Urbach, Anja; Baum, Eileen; Braun, Falko; Witte, Otto W.

doi:10.1177/0271678x16643736

Cited by 23 publications

(17 citation statements)

References 62 publications

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“…5). The widespread lobar or hemispheric effects of propagating spreading depolarizations are diverse and may include transient neurologic deficits, inflammation, neuroprotective preconditioning and neurogenesis (Gehrmann et al, 1993;Kobayashi et al, 1995;Dreier and Reiffurth, 2015;Urbach et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction

Hartings

York

Carroll

et al. 2017

Brain

108

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See Ghoshal and Claassen (doi:10.1093/brain/awx226) for a scientific commentary on this article. Early cortical infarcts are common in poor-grade patients after aneurysmal subarachnoid haemorrhage. There are no animal models of these lesions and mechanisms are unknown, although mass cortical spreading depolarizations are hypothesized as a requisite mechanism and clinical marker of infarct development. Here we studied acute sequelae of subarachnoid haemorrhage in the gyrencephalic brain of propofol-anaesthetized juvenile swine using subdural electrode strips (electrocorticography) and intraparenchymal neuromonitoring probes. Subarachnoid infusion of 1–2 ml of fresh blood at 200 µl/min over cortical sulci caused clusters of spreading depolarizations (count range: 12–34) in 7/17 animals in the ipsilateral but not contralateral hemisphere in 6 h of monitoring, without meaningful changes in other variables. Spreading depolarization clusters were associated with formation of sulcal clots (P< 0.01), a high likelihood of adjacent cortical infarcts (5/7 versus 2/10, P < 0.06), and upregulation of cyclooxygenase-2 in ipsilateral cortex remote from clots/infarcts. In a second cohort, infusion of 1 ml of clotted blood into a sulcus caused spreading depolarizations in 5/6 animals (count range: 4–20 in 6 h) and persistent thick clots with patchy or extensive infarction of circumscribed cortex in all animals. Infarcts were significantly larger after blood clot infusion compared to mass effect controls using fibrin clots of equal volume. Haematoxylin and eosin staining of infarcts showed well demarcated zones of oedema and hypoxic-ischaemic neuronal injury, consistent with acute infarction. The association of spreading depolarizations with early brain injury was then investigated in 23 patients [14 female; age (median, quartiles): 57 years (47, 63)] after repair of ruptured anterior communicating artery aneurysms by clip ligation (n = 14) or coiling (n = 9). Frontal electrocorticography [duration: 54 h (34, 66)] from subdural electrode strips was analysed over Days 0–3 after initial haemorrhage and magnetic resonance imaging studies were performed at ∼ 24–48 h after aneurysm treatment. Patients with frontal infarcts only and those with frontal infarcts and/or intracerebral haemorrhage were both significantly more likely to have spreading depolarizations (6/7 and 10/12, respectively) than those without frontal brain lesions (1/11, P’s < 0.05). These results suggest that subarachnoid clots in sulci/fissures are sufficient to induce spreading depolarizations and acute infarction in adjacent cortex. We hypothesize that the cellular toxicity and vasoconstrictive effects of depolarizations act in synergy with direct ischaemic effects of haemorrhage as mechanisms of infarct development. Results further validate spreading depolarizations as a clinical marker of early brain injury and establish a clinically relevant model to investigate causal pathologic sequences and potential therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction

Hartings

York

Carroll

et al. 2017

Brain

108

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“…1,6,7 Our current view is that SD facilitates neuronal injury in metabolically disturbed tissue, while it could be beneficial in surrounding tissue because it upregulates growth factors, stress response proteins and inflammatory mediators, [76][77][78][79] may have preconditioning actions 80 and may enhance plasticity 81 and regeneration. 82,83 Our study has some limitations: For example, (i) the group sizes were not sufficient to compare whether animals developing ET-1-induced SDs show significantly more cellular injury than animals not developing SDs. This should be studied in future experiments.…”

Section: Et-1-induced Sds In the Cerebellummentioning

confidence: 99%

Spreading depolarizations in the rat endothelin-1 model of focal cerebellar ischemia

Oliveira-Ferreira

Major

Przesdzing

et al. 2019

J Cereb Blood Flow Metab

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Focal brain ischemia is best studied in neocortex and striatum. Both show highly vulnerable neurons and high susceptibility to spreading depolarization (SD). Therefore, it has been hypothesized that these two variables generally correlate. However, this hypothesis is contradicted by findings in cerebellar cortex, which contains highly vulnerable neurons to ischemia, the Purkinje cells, but is said to be less susceptible to SD. Here, we found in the rat cerebellar cortex that elevated K+ induced a long-lasting depolarizing event superimposed with SDs. Cerebellar SDs resembled those in neocortex, but negative direct current (DC) shifts and regional blood flow responses were usually smaller. The K+ threshold for SD was higher in cerebellum than in previous studies in neocortex. We then topically applied endothelin-1 (ET-1) to the cerebellum, which is assumed to cause SD via vasoconstriction-induced focal ischemia. Although the blood flow decrease was similar to that in previous studies in neocortex, the ET-1 threshold for SD was higher. Quantitative cell counting found that the proportion of necrotic Purkinje cells was significantly higher in ET-1-treated rats than sham controls even if ET-1 had not caused SDs. Our results suggest that ischemic death of Purkinje cells does not require the occurrence of SD.

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“…Furthermore, neurogenesis could also be participating in cognitive improvement after Cop-1 immunization. With this regard, previous investigations have demonstrated that Cop-1 is capable of inducing neurogenesis [ 35 ], which could thereby modify cognitive function [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Copolymer-1 enhances cognitive performance in young adult rats

et al. 2018

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Cognitive impairment is a dysfunction observed as a sequel of various neurodegenerative diseases, as well as a concomitant element in the elderly stages of life. In clinical settings, this malfunction is identified as mild cognitive impairment. Previous studies have suggested that cognitive impairment could be the result of a reduction in the expression of brain-derived neurotrophic factor (BDNF) and/or immune dysfunction. Copolymer-1 (Cop-1) is an FDA-approved synthetic peptide capable of inducing the activation of Th2/3 cells, which are able to release BDNF, as well as to migrate and accumulate in the brain. In this study, we evaluated the effect of Cop-1 immunization on improvement of cognition in adult rats. For this purpose, we performed four experiments. We evaluated the effect of Cop-1 immunization on learning/memory using the Morris water maze for spatial memory and autoshaping for associative memory in 3- or 6-month-old rats. BDNF concentrations at the hippocampus were determined by ELISA. Cop-1 immunization induced a significant improvement of spatial memory and associative memory in 6-month-old rats. Likewise, Cop-1 improved spatial memory and associative memory when animals were immunized at 3 months and evaluated at 6 months old. Additionally, Cop-1 induced a significant increase in BDNF levels at the hippocampus. To our knowledge, the present investigation reports the first instance of Cop-1 treatment enhancing cognitive function in normal young adult rats, suggesting that Cop-1 may be a practical therapeutic strategy potentially useful for age- or disease-related cognitive impairment.

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Cortical spreading depolarization increases adult neurogenesis, and alters behavior and hippocampus-dependent memory in mice

Cited by 23 publications

References 62 publications

Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction

Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction

Spreading depolarizations in the rat endothelin-1 model of focal cerebellar ischemia

Copolymer-1 enhances cognitive performance in young adult rats

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