Nimodipine accelerates the restoration of functional hyperemia during spreading oligemia.

Spreading depolarization (SD) is assumed to be the pathophysiological correlate of migraine aura, leading to spreading depression of activity and a long-lasting vasoconstriction known as spreading oligemia. Furthermore, cerebrovascular reactivity is reversibly impaired after SD. Here, we explored the progressive restoration of impaired neurovascular coupling to somatosensory activation during spreading oligemia. Also, we evaluated whether nimodipine treatment accelerated the recovery of impaired neurovascular coupling after SD. Male, 4-9-month-old C57BL/6 mice (n = 11) were anesthetized with isoflurane (1%-1.5%), and SD was triggered with KCl through a burr hole made at the caudal parietal bone. EEG and cerebral blood flow (CBF) were recorded minimally invasively with a silver ball electrode and transcranial laser-Doppler flowmetry, rostral to SD elicitation. The L-type voltage-gated Ca2+ channel blocker nimodipine was administered i.p. (10 mg/kg). Whisker stimulation-related evoked potentials (EVPs) and functional hyperemia were assessed under isoflurane (0.1%)-medetomidine (0.1 mg/kg i.p.) anesthesia before, and repeatedly after SD, at 15-min intervals for 75 minutes. Nimodipine accelerated the recovery of CBF from spreading oligemia (time to full recovery, 52 ± 13 vs. 70 ± 8 min, nimodipine vs. control) and exhibited a tendency to shorten the duration of the SD-related EGG depression duration. The amplitudes of EVP and functional hyperemia were markedly reduced after SD, and progressively recovered over an hour post-SD. Nimodipine exerted no impact on EVP amplitude but consistently increased the absolute level of functional hyperemia from 20 min post-CSD (93 ± 11% vs. 66 ± 13%, nimodipine vs. control). A linear, positive correlation between EVP and functional hyperemia amplitude was skewed by nimodipine. In conclusion, nimodipine facilitated CBF restoration from spreading oligemia and the recovery of functional hyperemia post-SD, which were linked to a tendency of an accelerated return of spontaneous neural activity after SD. The use of nimodipine in migraine prophylaxis is suggested to be re-visited.

Transient Hypoperfusion to Ischemic/Anoxic Spreading Depolarization is Related to Autoregulatory Failure in the Rat Cerebral Cortex.

BACKGROUND: In ischemic stroke, cerebral autoregulation and neurovascular coupling may become impaired. The cerebral blood flow (CBF) response to spreading depolarization (SD) is governed by neurovascular coupling. SDs recur in the ischemic penumbra and reduce neuronal viability by the insufficiency of the CBF response. Autoregulatory failure and SD may coexist in acute brain injury. Here, we set out to explore the interplay between the impairment of cerebrovascular autoregulation, SD occurrence, and the evolution of the SD-coupled CBF response. METHODS: Incomplete global forebrain ischemia was created by bilateral common carotid artery occlusion in isoflurane-anesthetized rats, which induced ischemic SD (iSD). A subsequent SD was initiated 20-40 min later by transient anoxia SD (aSD), achieved by the withdrawal of oxygen from the anesthetic gas mixture for 4-5 min. SD occurrence was confirmed by the recording of direct current potential together with extracellular K+ concentration by intracortical microelectrodes. Changes in local CBF were acquired with laser Doppler flowmetry. Mean arterial blood pressure (MABP) was continuously measured via a catheter inserted into the left femoral artery. CBF and MABP were used to calculate an index of cerebrovascular autoregulation (rCBFx). In a representative imaging experiment, variation in transmembrane potential was visualized with a voltage-sensitive dye in the exposed parietal cortex, and CBF maps were generated with laser speckle contrast analysis. RESULTS: Ischemia induction and anoxia onset gave rise to iSD and aSD, respectively, albeit aSD occurred at a longer latency, and was superimposed on a gradual elevation of K+ concentration. iSD and aSD were accompanied by a transient drop of CBF (down to 11.9 ± 2.9 and 7.4 ± 3.6%, iSD and aSD), but distinctive features set the hypoperfusion transients apart. During iSD, rCBFx indicated intact autoregulation (rCBFx < 0.3). In contrast, aSD was superimposed on autoregulatory failure (rCBFx > 0.3) because CBF followed the decreasing MABP. CBF dropped 15-20 s after iSD, but the onset of hypoperfusion preceded aSD by almost 3 min. Taken together, the CBF response to iSD displayed typical features of spreading ischemia, whereas the transient CBF reduction with aSD appeared to be a passive decrease of CBF following the anoxia-related hypotension, leading to aSD. CONCLUSIONS: We propose that the dysfunction of cerebrovascular autoregulation that occurs simultaneously with hypotension transients poses a substantial risk of SD occurrence and is not a consequence of SD. Under such circumstances, the evolving SD is not accompanied by any recognizable CBF response, which indicates a severely damaged neurovascular coupling.

Comparative analysis of spreading depolarizations in brain slices exposed to osmotic or metabolic stress.

BACKGROUND: Recurrent spreading depolarizations (SDs) occur in stroke and traumatic brain injury and are considered as a hallmark of injury progression. The complexity of conditions associated with SD in the living brain encouraged researchers to study SD in live brain slice preparations, yet methodological differences among laboratories complicate integrative data interpretation. Here we provide a comparative evaluation of SD evolution in live brain slices, in response to selected SD triggers and in various media, under otherwise standardized experimental conditions. METHODS: Rat live coronal brain slices (350 µm) were prepared (n = 51). Hypo-osmotic medium (Na+ content reduced from 130 to 60 mM, HM) or oxygen-glucose deprivation (OGD) were applied to cause osmotic or ischemic challenge. Brain slices superfused with artificial cerebrospinal fluid (aCSF) served as control. SDs were evoked in the control condition with pressure injection of KCl or electric stimulation. Local field potential (LFP) was recorded via an intracortical glass capillary electrode, or intrinsic optical signal imaging was conducted at white light illumination to characterize SDs. TTC and hematoxylin-eosin staining were used to assess tissue damage. RESULTS: Severe osmotic stress or OGD provoked a spontaneous SD. In contrast with SDs triggered in aCSF, these spontaneous depolarizations were characterized by incomplete repolarization and prolonged duration. Further, cortical SDs under HM or OGD propagated over the entire cortex and occassionally invaded the striatum, while SDs in aCSF covered a significantly smaller cortical area before coming to a halt, and never spread to the striatum. SDs in HM displayed the greatest amplitude and the most rapid propagation velocity. Finally, spontaneous SD in HM and especially under OGD was followed by tissue injury. CONCLUSIONS: While the failure of Na+/K+ ATP-ase is thought to impair tissue recovery from OGD-related SD, the tissue swelling-related hyper excitability and the exhaustion of astrocyte buffering capacity are suggested to promote SD evolution under osmotic stress. In contrast with OGD, SD propagating under hypo-osmotic condition is not terminal, yet it is associated with irreversible tissue injury. Further investigation is required to understand the mechanistic similarities or differences between the evolution of SDs spontaneously occurring in HM and under OGD.

Astrocyte Ca2+ Waves and Subsequent Non-Synchronized Ca2+ Oscillations Coincide with Arteriole Diameter Changes in Response to Spreading Depolarization.

Spreading depolarization (SD) is a wave of mass depolarization that causes profound perfusion changes in acute cerebrovascular diseases. Although the astrocyte response is secondary to the neuronal depolarization with SD, it remains to be explored how glial activity is altered after the passage of SD. Here, we describe post-SD high frequency astrocyte Ca2+ oscillations in the mouse somatosensory cortex. The intracellular Ca2+ changes of SR101 labeled astrocytes and the SD-related arteriole diameter variations were simultaneously visualized by multiphoton microscopy in anesthetized mice. Post-SD astrocyte Ca2+ oscillations were identified as Ca2+ events non-synchronized among astrocytes in the field of view. Ca2+ oscillations occurred minutes after the Ca2+ wave of SD. Furthermore, fewer astrocytes were involved in Ca2+ oscillations at a given time, compared to Ca2+ waves, engaging all astrocytes in the field of view simultaneously. Finally, our data confirm that astrocyte Ca2+ waves coincide with arteriolar constriction, while post-SD Ca2+ oscillations occur with the peak of the SD-related vasodilation. This is the first in vivo study to present the post-SD astrocyte Ca2+ oscillations. Our results provide novel insight into the spatio-temporal correlation between glial reactivity and cerebral arteriole diameter changes behind the SD wavefront.

Large-conductance Ca2+-activated potassium channels are potently involved in the inverse neurovascular response to spreading depolarization.

Recurrent spreading depolarizations occur in the cerebral cortex from minutes up to weeks following acute brain injury. Clinical evidence suggests that the immediate reduction of cerebral blood flow in response to spreading depolarization importantly contributes to lesion progression as the wave propagates over vulnerable tissue zones, characterized by potassium concentration already elevated prior to the passage of spreading depolarization. Here we demonstrate with two-photon microscopy in anesthetized mice that initial vasoconstriction in response to SD triggered experimentally with 1 M KCl is coincident in space and time with the large extracellular accumulation of potassium, as shown with a potassium indicator fluorescent dye. Moreover, pharmacological manipulations in combination with the use of potassium-sensitive microelectrodes suggest that large-conductance Ca2+-activated potassium (BK) channels and L-type voltage-gated calcium channels play significant roles in the marked initial vasoconstriction under elevated baseline potassium. We propose that potassium efflux through BK channels is a central component in the devastating neurovascular effects of spreading depolarizations in tissue at risk.

Age or ischemia uncouples the blood flow response, tissue acidosis, and direct current potential signature of spreading depolarization in the rat brain.

Spreading depolarization (SD) events contribute to lesion maturation in the acutely injured human brain. Neurodegeneration related to SD is thought to be caused by the insufficiency of the cerebral blood flow (CBF) response; yet the mediators of the CBF response, or their deficiency in the aged or ischemic cerebral cortex, remain the target of intensive research. Here, we postulated that tissue pH effectively modulates the magnitude of hyperemia in response to SD, the coupling of which is prone to be dysfunctional in the aged or ischemic cerebral cortex. To test this hypothesis, we conducted systematic correlation analysis between the direct current (DC) potential signature of SD, SD-associated tissue acidosis, and hyperemic element of the CBF response in the isoflurane-anesthetized, young or old, and intact or ischemic rat cerebral cortex. The data demonstrate that the amplitude of the SD-related DC potential shift, tissue acidosis, and hyperemia are tightly coupled in the young intact cortex; ischemia and old age uncouples the amplitude of hyperemia from the amplitude of the DC potential shift and acidosis; the duration of the DC potential shift, hyperemia and acidosis positively correlate under ischemia alone; and old age disproportionally elongates the duration of acidosis with respect to the DC potential shift and hyperemia under ischemia. The coincidence of the variables supports the view that local CBF regulation with SD must have an effective metabolic component, which becomes dysfunctional with age or under ischemia. Finally, the known age-related acceleration of ischemic neurodegeneration may be promoted by exaggerated tissue acidosis.NEW & NOTEWORTHY The hyperemic element of the cerebral blood flow response to spreading depolarization is effectively modulated by tissue pH in the young intact rat cerebral cortex. This coupling becomes dysfunctional with age or under ischemia, and tissue acidosis lasts disproportionally longer in the aged cortex, making the tissue increasingly more vulnerable.

Systemic administration of l-kynurenine sulfate induces cerebral hypoperfusion transients in adult C57Bl/6 mice.

The kynurenine pathway is a cascade of enzymatic steps generating biologically active compounds. l-kynurenine (l-KYN) is a central metabolite of tryptophan degradation. In the mammalian brain, l-KYN is partly converted to kynurenic acid (KYNA), which exerts multiple effects on neurotransmission. Recently, l-KYN or one of its derivatives were attributed a direct role in the regulation of the systemic circulation. l-KYN dilates arterial blood vessels during sepsis in rats, while it increases cerebral blood flow (CBF) in awake rabbits. Therefore, we hypothesized that acute elevation of systemic l-KYN concentration may exert potential effects on mean arterial blood pressure (MABP) and on resting CBF in the mouse brain. C57Bl/6 male mice were anesthetized with isoflurane, and MABP was monitored in the femoral artery, while CBF was assessed through the intact parietal bone with the aid of laser speckle contrast imaging. l-KYN sulfate (l-KYNs) (300mg/kg, i.p.) or vehicle was administered intraperitoneally. Subsequently, MABP and CBF were continuously monitored for 2.5h. In the control group, MABP and CBF were stable (69±4mmHg and 100±5%, respectively) throughout the entire data acquisition period. In the l-KYNs-treated group, MABP was similar to that, of control group (73±6mmHg), while hypoperfusion transients of 22±6%, lasting 7±3min occurred in the cerebral cortex over the first 60-120min following drug administration. In conclusion, the systemic high-dose of l-KYNs treatment destabilizes resting CBF by inducing a number of transient hypoperfusion events. This observation indicates the careful consideration of the dose of l-KYN administration by interpreting the effect of kynurenergic manipulation on brain function. By planning clinical trials basing on kynurenergic manipulation possible vascular side effects should also be considered.

Collateral is brain: Low perfusion triggers spreading depolarization and futile reperfusion after acute ischemic stroke.

Futile reperfusion is a phenomenon of inadequate perfusion despite successful recanalization after acute ischemic stroke (AIS). It is associated with poor patient outcomes and has received increasing interest due to its clinical diagnosis becoming more common. However, the underlying mechanisms remain elusive, and experimental studies are focused on the pathological background of futile reperfusion. Our recent study has confirmed that poor primary collateralization plays a crucial role in the insufficiency of reperfusion after AIS in mice. Specifically, the absence of primary collaterals in the circle of Willis (CoW) promoted the development of spreading depolarizations (SDs) during AIS. In our experimental stroke model, the occurrence of SDs during ischemia always predicted futile reperfusion. Conversely, in mice with a complete CoW, no SDs were observed, and reperfusion was complete. Importantly, the human CoW displays variation in the primary collaterals in approximately 50% of the population. Therefore, futile reperfusion may result from SD evolution in AIS patients. Our purpose here is to emphasize the crucial role of SD in the development of futile reperfusion. We propose that adequate collateral recruitment can prevent SD occurrence, leading to improved reperfusion and AIS outcomes.

Nimodipine inhibits spreading depolarization, ischemic injury, and neuroinflammation in mouse live brain slice preparations.

Nimodipine is used to prevent delayed ischemic deficit in patients with aneurysmal subarachnoid hemorrhage (aSAH). Spreading depolarization (SD) is recognized as a factor in the pathomechanism of aSAH and other acute brain injuries. Although nimodipine is primarily known as a cerebral vasodilator, it may have a more complex mechanism of action due to the expression of its target, the L-type voltage-gated calcium channels (LVGCCs) in various cells in neural tissue. This study was designed to investigate the direct effect of nimodipine on SD, ischemic tissue injury, and neuroinflammation. SD in control or nimodipine-treated live mouse brain slices was induced under physiological conditions using electrical stimulation, or by subjecting the slices to hypo-osmotic stress or mild oxygen-glucose deprivation (mOGD). SD was recorded applying local field potential recording or intrinsic optical signal imaging. Histological analysis was used to estimate tissue injury, the number of reactive astrocytes, and the degree of microglia activation. Nimodipine did not prevent SD occurrence in mOGD, but it did reduce the rate of SD propagation and the cortical area affected by SD. In contrast, nimodipine blocked SD occurrence in hypo-osmotic stress, but had no effect on SD propagation. Furthermore, nimodipine prevented ischemic injury associated with SD in mOGD. Nimodipine also exhibited anti-inflammatory effects in mOGD by reducing reactive astrogliosis and microglial activation. The results demonstrate that nimodipine directly inhibits SD, independent of nimodipine's vascular effects. Therefore, the use of nimodipine may be extended to treat acute brain injuries where SD plays a central role in injury progression.

Nimodipine augments cerebrovascular reactivity in aging but runs the risk of local perfusion reduction in acute cerebral ischemia.

Introduction: The efficacy of cerebrovascular reactivity (CVR) is taken as an indicator of cerebrovascular health. Methods and Results: We found that CVR tested with the inhalation of 10 % CO2 declined in the parietal cortex of 18-20-month-old rats. The CVR deficit in old rats was coincident with cerebrovascular smooth muscle cell and astrocyte senescence, revealed by the immuno-labeling of the cellular senescence marker p16 in these cells. In a next series of experiments, CVR was severely impaired in the acute phase of incomplete global forebrain ischemia produced by the bilateral occlusion of the common carotid arteries in young adult rats. In acute ischemia, CVR impairment often manifested as a perfusion drop rather than blood flow elevation in response to hypercapnia. Next, nimodipine, an L-type voltage-gated calcium channel antagonist was administered topically to rescue CVR in both aging, and cerebra ischemia. Nimodipine augmented CVR in the aged brain, but worsened CVR impairment in acute cerebral ischemia. Discussion: A careful evaluation of benefits and side effects of nimodipine is recommended, especially in acute ischemic stroke.

Spreading depolarization causes reperfusion failure after cerebral ischemia.

Despite successful recanalization, reperfusion failure associated with poor neurological outcomes develops in half of treated stroke patients. We explore here whether spreading depolarization (SD) is a predictor of reperfusion failure. Global forebrain ischemia/reperfusion was induced in male and female C57BL/6 mice (n = 57). SD and cerebral blood flow (CBF) changes were visualized with transcranial intrinsic optical signal and laser speckle contrast imaging. To block SD, MK801 was applied (n = 26). Neurological deficit, circle of Willis (CoW) anatomy and neuronal injury were evaluated 24 hours later. SD emerged after ischemia onset in one or both hemispheres under a perfusion threshold (CBF drop to 21.1 ± 4.6 vs. 33.6 ± 4.4%, SD vs. no SD). The failure of later reperfusion (44.4 ± 12.5%) was invariably linked to previous SD. In contrast, reperfusion was adequate (98.9 ± 7.4%) in hemispheres devoid of SD. Absence of the P1 segment of the posterior cerebral artery in the CoW favored SD occurrence and reperfusion failure. SD occurrence and reperfusion failure were associated with poor neurologic function, and neuronal necrosis 24 hours after ischemia. The inhibition of SD significantly improved reperfusion. SD occurrence during ischemia impairs later reperfusion, prognosticating poor neurological outcomes. The increased likelihood of SD occurrence is predicted by inadequate collaterals.

Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci.

Spreading depolarizations (SDs) indicate injury progression and predict worse clinical outcome in acute brain injury. We demonstrate in rodents that acute brain swelling upon cerebral ischemia impairs astroglial glutamate clearance and increases the tissue area invaded by SD. The cytotoxic extracellular glutamate accumulation (>15 µM) predisposes an extensive bulk of tissue (4-5 mm2) for a yet undescribed simultaneous depolarization (SiD). We confirm in rat brain slices exposed to osmotic stress that SiD is the pathological expansion of prior punctual SD foci (0.5-1 mm2), is associated with astrocyte swelling, and triggers oncotic neuron death. The blockade of astrocytic aquaporin-4 channels and Na+/K+/Cl- co-transporters, or volume-regulated anion channels mitigated slice edema, extracellular glutamate accumulation (<10 µM) and SiD occurrence. Reversal of slice swelling by hyperosmotic mannitol counteracted glutamate accumulation and prevented SiD. In contrast, inhibition of glial metabolism or inhibition of astrocyte glutamate transporters reproduced the SiD phenotype. Finally, we show in the rodent water intoxication model of cytotoxic edema that astrocyte swelling and altered astrocyte calcium waves are central in the evolution of SiD. We discuss our results in the light of evidence for SiD in the human cortex. Our results emphasize the need of preventive osmotherapy in acute brain injury.

Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions.

Microglia, the main immunocompetent cells of the brain, regulate neuronal function, but their contribution to cerebral blood flow (CBF) regulation has remained elusive. Here, we identify microglia as important modulators of CBF both under physiological conditions and during hypoperfusion. Microglia establish direct, dynamic purinergic contacts with cells in the neurovascular unit that shape CBF in both mice and humans. Surprisingly, the absence of microglia or blockade of microglial P2Y12 receptor (P2Y12R) substantially impairs neurovascular coupling in mice, which is reiterated by chemogenetically induced microglial dysfunction associated with impaired ATP sensitivity. Hypercapnia induces rapid microglial calcium changes, P2Y12R-mediated formation of perivascular phylopodia, and microglial adenosine production, while depletion of microglia reduces brain pH and impairs hypercapnia-induced vasodilation. Microglial actions modulate vascular cyclic GMP levels but are partially independent of nitric oxide. Finally, microglial dysfunction markedly impairs P2Y12R-mediated cerebrovascular adaptation to common carotid artery occlusion resulting in hypoperfusion. Thus, our data reveal a previously unrecognized role for microglia in CBF regulation, with broad implications for common neurological diseases.

N,N-Dimethyltryptamine attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain.

Dimethyltryptamine (DMT), an endogenous ligand of sigma-1 receptors (Sig-1Rs), acts against systemic hypoxia, but whether DMT may prevent cerebral ischemic injury is unexplored. Here global forebrain ischemia was created in anesthetized rats and aggravated with the induction of spreading depolarizations (SDs) and subsequent short hypoxia before reperfusion. Drugs (DMT, the selective Sig-1R agonist PRE-084, the Sig-1R antagonist NE-100, or the serotonin receptor antagonist asenapine) were administered intravenously alone or in combination while physiological variables and local field potential from the cerebral cortex was recorded. Neuroprotection and the cellular localization of Sig-1R were evaluated with immunocytochemistry. Plasma and brain DMT content was measured by 2D-LC-HRMS/MS. The affinity of drugs for cerebral Sig-1R was evaluated with a radioligand binding assay. Both DMT and PRE-084 mitigated SDs, counteracted with NE-100. Further, DMT attenuated SD when co-administered with asenapine, compared to asenapine alone. DMT reduced the number of apoptotic and ferroptotic cells and supported astrocyte survival. The binding affinity of DMT to Sig-1R matched previously reported values. Sig-1Rs were associated with the perinuclear cytoplasm of neurons, astrocytes and microglia, and with glial processes. According to these data, DMT may be considered as adjuvant pharmacological therapy in the management of acute cerebral ischemia.

Tissue Acidosis Associated with Ischemic Stroke to Guide Neuroprotective Drug Delivery.

Ischemic stroke is a leading cause of death and disability worldwide. Yet, the effective therapy of focal cerebral ischemia has been an unresolved challenge. We propose here that ischemic tissue acidosis, a sensitive metabolic indicator of injury progression in cerebral ischemia, can be harnessed for the targeted delivery of neuroprotective agents. Ischemic tissue acidosis, which represents the accumulation of lactic acid in malperfused brain tissue is significantly exacerbated by the recurrence of spreading depolarizations. Deepening acidosis itself activates specific ion channels to cause neurotoxic cellular Ca2+ accumulation and cytotoxic edema. These processes are thought to contribute to the loss of the ischemic penumbra. The unique metabolic status of the ischemic penumbra has been exploited to identify the penumbra zone with imaging tools. Importantly, acidosis in the ischemic penumbra may also be used to guide therapeutic intervention. Agents with neuroprotective promise are suggested here to be delivered selectively to the ischemic penumbra with pH-responsive smart nanosystems. The administered nanoparticels release their cargo in acidic tissue environment, which reliably delineates sites at risk of injury. Therefore, tissue pH-targeted drug delivery is expected to enrich sites of ongoing injury with the therapeutical agent, without the risk of unfavorable off-target effects.

Chitosan nanoparticles release nimodipine in response to tissue acidosis to attenuate spreading depolarization evoked during forebrain ischemia.

Stroke is an important cause of mortality and disability. Treatment options are limited, therefore the progress in this regard is urgently needed. Nimodipine, an L-type voltage-gated calcium channel antagonist dilates cerebral arterioles, but its systemic administration may cause potential side effects. We have previously constructed chitosan nanoparticles as drug carriers, which release nimodipine in response to decreasing pH typical of cerebral ischemia. Here we have set out to evaluate this nanomedical approach to deliver nimodipine selectively to acidic ischemic brain tissue. After washing a nanoparticle suspension with or without nimodipine (100 µM) on the exposed brain surface of anesthetized rats (n = 18), both common carotid arteries were occluded to create forebrain ischemia. Spreading depolarizations (SDs) were elicited by 1M KCl to deepen the ischemic insult. Local field potential, cerebral blood flow (CBF) and tissue pH were recorded from the cerebral cortex. Microglia activation and neuronal survival were evaluated in brain sections by immunocytochemistry. Ischemia-induced tissue acidosis initiated nimodipine release from nanoparticles, confirmed by the significant elevation of baseline CBF (47.8 ±â€¯23.7 vs. 29.3 ±â€¯6.96%). Nimodipine shortened the duration of both SD itself (48.07 ±â€¯23.29 vs. 76.25 ±â€¯17.2 s), and the associated tissue acidosis (65.46 ±â€¯20.2 vs. 138.3 ±â€¯66.07 s), moreover it enhanced the SD-related hyperemia (48.15 ±â€¯42.04 vs. 17.29 ±â€¯11.03%). Chitosan nanoparticles did not activate microglia. The data support the concept that tissue acidosis linked to cerebral ischemia can be employed as a trigger for targeted drug delivery. Nimodipine-mediated vasodilation and SD inhibition can be achieved by pH-responsive chitosan nanoparticles applied directly to the brain surface.

Microglia alter the threshold of spreading depolarization and related potassium uptake in the mouse brain.

Selective elimination of microglia from the brain was shown to dysregulate neuronal Ca2+ signaling and to reduce the incidence of spreading depolarization (SD) during cerebral ischemia. However, the mechanisms through which microglia interfere with SD remained unexplored. Here, we identify microglia as essential modulators of the induction and evolution of SD in the physiologically intact brain in vivo. Confocal- and super-resolution microscopy revealed that a series of SDs induced rapid morphological changes in microglia, facilitated microglial process recruitment to neurons and increased the density of P2Y12 receptors (P2Y12R) on recruited microglial processes. In line with this, depolarization and hyperpolarization during SD were microglia- and P2Y12R-dependent. An absence of microglia was associated with altered potassium uptake after SD and increased the number of c-fos-positive neurons, independently of P2Y12R. Thus, the presence of microglia is likely to be essential to maintain the electrical elicitation threshold and to support the full evolution of SD, conceivably by interfering with the extracellular potassium homeostasis of the brain through sustaining [K+]e re-uptake mechanisms.

Susceptibility of the cerebral cortex to spreading depolarization in neurological disease states: The impact of aging.

Secondary injury following acute brain insults significantly contributes to poorer neurological outcome. The spontaneous, recurrent occurrence of spreading depolarization events (SD) has been recognized as a potent secondary injury mechanism in subarachnoid hemorrhage, malignant ischemic stroke and traumatic brain injury. In addition, SD is the underlying mechanism of the aura symptoms of migraineurs. The susceptibility of the nervous tissue to SD is subject to the metabolic status of the tissue, the ionic composition of the extracellular space, and the functional status of ion pumps, voltage-gated and other cation channels, glutamate receptors and excitatory amino acid transporters. All these mechanisms tune the excitability of the nervous tissue. Aging has also been found to alter SD susceptibility, which appears to be highest at young adulthood, and decline over the aging process. The lower susceptibility of the cerebral gray matter to SD in the old brain may be caused by the age-related impairment of mechanisms implicated in ion translocations between the intra- and extracellular compartments, glutamate signaling and surplus potassium and glutamate clearance. Even though the aging nervous tissue is thus less able to sustain SD, the consequences of SD recurrence in the old brain have proven to be graver, possibly leading to accelerated lesion maturation. Taken that recurrent SDs may pose an increased burden in the aging injured brain, the benefit of therapeutic approaches to restrict SD generation and propagation may be particularly relevant for elderly patients.

[The role of multimodal postoperative analgesia after primary hip arthroplasty]. / A multimodális posztoperatív fájdalomcsillapítás szerepe primer csípoízületi arthroplasticában.

Introduction: Due to the increasing number of arthroplasties, the number of post-operative hospital days was reduced and the rate of rehabilitation accelerated. For this, proper postoperative analgesia is essential and the multimodal pain relief is an excellent tool. Aim: The aim of our study was to compare postoperative functional results, postoperative pain levels, and opioid analgesic needs of patients who received conventional and novel analgesic treatments. Method: In our prospective study, 81 patients were enrolled who underwent primary hip prosthesis surgery in our institution between February 2017 and January 2018. Of the randomized patients, 38 were in the control group and 43 in the multimodal pain group. We have tested their analgesic needs and the subjective pain levels of patients with the help of the visual analog scale (VAS). Results: Patients receiving multimodal pain relief had significantly lower opioid analgesic requirements and significantly lower VAS values assessed at 6 hours, and 3 and 4 days postoperatively. In addition, the patients in this group stayed in the hospital for a significantly shorter time after surgery. Conclusions: Based on our experience, multimodal pain relief in one-sided primary hip joint arthroplasty significantly reduced the patients' postoperative subjective pain sensation and pain killer consumptions. Orv Hetil. 2019; 160(52): 2054-2060.