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Interspecies variability and poor clinical translation from rodent studies indicate that large gyrencephalic animal stroke models are urgently needed. We present a proof-of-principle study describing an alternative animal model of malignant infarction of the middle cerebral artery (MCA) in the common pig and illustrate some of its potential applications. We report on metabolic patterns, ionic profile, brain partial pressure of oxygen (PtiO2), expression of sulfonylurea receptor 1 (SUR1), and the transient receptor potential melastatin 4 (TRPM4). A 5-hour ischemic infarct of the MCA territory was performed in 5 2.5-to-3-month-old female hybrid pigs (Large White x Landrace) using a frontotemporal approach. The core and penumbra areas were intraoperatively monitored to determine the metabolic and ionic profiles. To determine the infarct volume, 2,3,5-triphenyltetrazolium chloride staining and immunohistochemistry analysis was performed to determine SUR1 and TRPM4 expression. PtiO2 monitoring showed an abrupt reduction in values close to 0 mmHg after MCA occlusion in the core area. Hourly cerebral microdialysis showed that the infarcted tissue was characterized by reduced concentrations of glucose (0.03 mM) and pyruvate (0.003 mM) and increases in lactate levels (8.87mM), lactate-pyruvate ratio (4202), glycerol levels (588 μM), and potassium concentration (27.9 mmol/L). Immunohistochemical analysis showed increased expression of SUR1-TRPM4 channels. The aim of the present proof-of-principle study was to document the feasibility of a large animal model of malignant MCA infarction by performing transcranial occlusion of the MCA in the common pig, as an alternative to lisencephalic animals. This model may be useful for detailed studies of cerebral ischemia mechanisms and the development of neuroprotective strategies.

[...]DRP1 silencing resulted in an approximately 50% decrease in the number of individual mitochondria per ROI, both in wild-type and dynamin triple-knockout cells (Fig. 1l). The kinetics of mitochondrial fission were also indistinguishable between scrambled control and DNM2-knockdown HeLa cells (Extended Data Fig. 1u; Supplementary Video 2). [...]the steady-state level of mitochondrial fission or fusion is unaltered in dynamin triple-knockout and DNM2-knockdown cells, under basal culture conditions. [...]our results show that dynamin proteins are not required for mitochondrial fission, under both basal and stimulated conditions. [...]the selection of cellular models is probably not an explanation for why our data are in contrast with the earlier report that used HeLa and Cos7 cells with knockdown of DNM2 as experimental model5.

For decades, lactate has been considered an excellent biomarker for oxygen limitation and therefore of organ ischemia. The aim of the present study was to evaluate the frequency of increased brain lactate levels and the LP ratio (LPR) in a cohort of patients with severe or moderate traumatic brain injury (TBI) subjected to brain microdialysis monitoring to analyze the agreement between these two biomarkers and to indicate brain energy metabolism dysfunction. Forty-six patients with an admission Glasgow coma scale score of ≤13 after resuscitation admitted to a dedicated 10-bed Neurotraumatology Intensive Care Unit were included, and 5305 verified samples of good microdialysis data were analyzed. Lactate levels were above 2.5 mmol/L in 56.9% of the samples. The relationships between lactate and the LPR could not be adequately modeled by any linear or non-linear model. Neither Cohen's kappa nor Gwet's statistic showed an acceptable agreement between both biomarkers to classify the samples in regard to normal or abnormal metabolism. The dataset was divided into four patterns defined by the lactate concentrations and the LPR. A potential interpretation for these patterns is suggested and discussed. Pattern 4 (low pyruvate levels) was found in 10.7% of the samples and was characterized by a significantly low concentration of brain glucose compared with the other groups. Our study shows that metabolic abnormalities are frequent in the macroscopically normal brain in patients with traumatic brain injuries and a very poor agreement between lactate and the LPR when classifying metabolism. The concentration of lactate in the dialysates must be interpreted while taking into consideration the LPR to distinguish between anaerobic metabolism and aerobic hyperglycolysis.

Lysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain poorly understood. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and non-apoptotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified by in vivo magnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking impaired lysosomal acidification, mitochondrial malfunction and inflammation in vivo.

Objective Spreading depolarizations (SDs) have been described in patients with ischemic and haemorrhagic stroke, traumatic brain injury, and migraine with aura, among other conditions. The exact pathophysiological mechanism of SDs is not yet fully established. Our aim in this study was to evaluate the relationship between the electrocorticography (ECoG) findings of SDs and/or epileptiform activity and subsequent epilepsy and electroclinical outcome. Methods This was a prospective observational study of 39 adults, 17 with malignant middle cerebral artery infarction (MMCAI) and 22 with traumatic brain injury, who underwent decompressive craniectomy and multimodal neuromonitoring including ECoG in penumbral tissue. Serial electroencephalography (EEG) recordings were obtained for all surviving patients. Functional disability at 6 and 12 months after injury were assessed using the Barthel, modified Rankin (mRS), and Extended Glasgow Outcome (GOS-E) scales. Results SDs were recorded in 58.9% of patients, being more common—particularly those of isoelectric type—in patients with MMCAI ( p  < 0.04). At follow-up, 74.7% of patients had epileptiform abnormalities on EEG and/or seizures. A significant correlation was observed between the degree of preserved brain activity on EEG and disability severity ( R [mRS]: + 0.7, R [GOS-E, Barthel]: − 0.6, p  < 0.001), and between the presence of multifocal epileptiform abnormalities on EEG and more severe disability on the GOS-E at 6 months ( R : − 0.3, p  = 0.03) and 12 months ( R : − 0.3, p  = 0.05). Patients with more SDs and higher depression ratios scored worse on the GOS-E ( R : − 0.4 at 6 and 12 months) and Barthel ( R : − 0.4 at 6 and 12 months) disability scales ( p  < 0.05). The number of SDs ( p  = 0.064) and the depression ratio ( p  = 0.1) on ECoG did not show a statistically significant correlation with late epilepsy. Conclusions SDs are common in the cortex of ischemic or traumatic penumbra. Our study suggests an association between the presence of SDs in the acute phase and worse long-term outcome, although no association with subsequent epilepsy was found. More comprehensive studies, involving ECoG and EEG could help determine their association with epileptogenesis.

Significant controversy exists regarding the potential clinical benefit of normobaric hyperoxia (NBO) in patients with traumatic brain injury (TBI). This study consisted of two aims: 1) to assess whether NBO improves brain oxygenation and metabolism and 2) to determine whether this therapy may increase the risk of oxidative stress (OxS), using 8-iso-Prostaglandin F2α (PGF2α) as a biomarker. Thirty-one patients with a median admission Glasgow Coma Scale score of 4 (min: 3, max: 12) were monitored with cerebral microdialysis and brain tissue oxygen sensors and treated with fraction of inspired oxygen (FiO2) of 1.0 for 4 h. Patients were divided into two groups according to the area monitored by the probes: normal injured brain and traumatic penumbra/traumatic core. NBO maintained for 4 h did not induce OxS in patients without preOxS at baseline, except in one case. However, for patients in whom OxS was detected at baseline, NBO induced a significant increase in 8-iso-PGF2α. The results of our study showed that NBO did not change energy metabolism in the whole group of patients. In the five patients with brain lactate concentration ([Lac]brain) > 3.5 mmol/L at baseline, NBO induced a marked reduction in both [Lac]brain and lactate-to-pyruvate ratio. Although these differences were not statistically significant, together with the results of our previous study, they suggest that TBI patients would benefit from receiving NBO when they show indications of disturbed brain metabolism. These findings, in combination with increasing evidence that TBI metabolic crises are common without brain ischemia, open new possibilities for the use of this accessible therapeutic strategy in TBI patients.

Traumatic brain injury (TBI) and ischemic stroke cause a variable disruption of ionic homeostasis and massive ionic fluxes with subsequent osmotic water movement across the cells that causes edema, brain swelling, and deformation of the damaged tissue. Although cerebral microdialysis (CMD) has been used to study the brain neurochemistry, the ionic profiles of brain interstitial space fluid have rarely been reported in humans. We studied the ionic profile in injured areas of the brain by using CMD. As a control group, we included seven patients who had undergone surgical treatment of posterior fossa lesions, without abnormalities in the supratentorial compartment. Inductively coupled plasma mass spectrometry (ICP-MS) was used for ion determination. No significant differences were found in the [Na+]o, [K+]o, and [Cl-]o between normal injured brains and controls. The ionic profile of the ischemic core was characterized by very high [K+]o and an increase in [Na+]o, whereas [Cl-]o was linearly related to [Na+]o. In the traumatic core (TC), significantly higher levels of [Na+]o, [Cl-]o, and [K+]o were found. The main finding in the penumbra was a completely normal ionic profile for [Na+]o and [K+]o in 60% of the samples. ICP-MS coupled to ionic assays creates a powerful tool for a better understanding of the complex ionic disturbances that occur after severe TBI and ischemic stroke.

Our aim is to determine whether the ionic concentration in brain microdialysate enables calculations of the actual Na+, K+, and Cl− concentrations in vitro and whether this method can be applied to determine the ionic concentrations in the brain extracellular fluid. We designed an experiment using CMA-71 probes (M Dialysis, Stockholm, Sweden) and the standard conditions used in a clinical setting. Nine CMA-71 probes were inserted in different matrices and perfused with mock cerebrospinal fluid containing 3% albumin at the standard infusion rate used in the clinical setting (0.3 μL/min). Microvials were replaced every 12 h, and the ionic concentrations, both in the dialysate and the matrix, were analyzed. For each ion, scatter plots were built, with [Na+], [K+], and [Cl−] in the dialysate as the predictor variables and the matrix concentrations as the outcome variables. A linear regression model allowed us to calculate the true ionic concentrations in the matrix. To demonstrate the feasibility of the method, we present the calculated ionic profile of one patient with a malignant infarction and a second with a severe traumatic brain injury. Our results confirm that the ionic concentration in microdialysate can be used to calculate the true concentrations of ions in a matrix and the actual concentrations in the extracellular fluid. Microdialysis offers the unique possibility of monitoring the dynamic changes of ions in the brain over time and opens a new avenue to explore the brain's ionic profile, its changes in brain edema, and how this profile can be modified with different therapies.