Pericytes in the brain and heart: functional roles and response to ischemia and reperfusion.

In the last 20 years there has been a revolution in our understanding of how blood flow is regulated in many tissues. Whereas it used to be thought that essentially all blood flow control occurred at the arteriole level, it is now recognised that control of capillary blood flow by contractile pericytes plays a key role both in regulating blood flow physiologically and in reducing it in clinically-relevant pathological conditions. In this article we compare and contrast how brain and cardiac pericytes regulate cerebral and coronary blood flow, focusing mainly on the pathological events of cerebral and cardiac ischemia.

The Brain, the Eating Plate, and the Gut Microbiome: Partners in Migraine Pathogenesis.

This review summarizes the relationship between diet, the gut microbiome, and migraine. Key findings reveal that certain dietary factors, such as caffeine and alcohol, can trigger migraine, while nutrients like magnesium and riboflavin may help alleviate migraine symptoms. The gut microbiome, through its influence on neuroinflammation (e.

The effect of P2X7 antagonism on subcortical spread of optogenetically-triggered cortical spreading depression and neuroinflammation.

Migraine is a neurological disorder characterized by episodes of severe headache. Cortical spreading depression (CSD), the electrophysiological equivalent of migraine aura, results in opening of pannexin 1 megachannels that release ATP and triggers parenchymal neuroinflammatory signaling cascade in the cortex. Migraine symptoms suggesting subcortical dysfunction bring subcortical spread of CSD under the light.

FGF2 gene's antisense protein, NUDT6, plays a depressogenic role by promoting inflammation and suppressing neurogenesis without altering FGF2 signalling.

Fibroblast growth factor-2 (FGF2) is involved in the regulation of affective behaviour and shows antidepressant effects through the Akt and extracellular signal regulated kinase (ERK) 1/2 pathways. Nudix hydrolase 6 (NUDT6) protein is encoded from FGF2 gene's antisense strand and its role in the regulation of affective behaviour is unknown. Here, we overexpressed NUDT6 in the hippocampus and investigated its behavioural effects and the underlying molecular mechanisms affecting the behaviour.

The Effect of Inhibition of Perisynaptic Astrocyte Glycogen Utilization on Depression-Like Behavior.

Objective: Under physiological conditions, astrocytes produce lactate to meet the increased synaptic energy demand due to neuronal activity. In the light of the findings showing that this process is disrupted in the pathophysiology of major depression, the aim of this study is to investigate the effect of pharmacological inhibition of perisynaptic astrocyte glycogen utilization on anxiety-like behavior and depression-like behavior in female and male mice.

Methods: In this study, DAB (1,4-dideoxy-1,4-imino-D-arabinitol), which is an inhibitor of glycogen breaking enzyme glycogen phosphorylase, was intrahippocampally administered to 15 female and 14 male Swiss albino mice, while 15 female and 12 male Swiss albino mice received intrahippocampal saline injections.

Vesicular HMGB1 release from neurons stressed with spreading depolarization enables confined inflammatory signaling to astrocytes.

The role of high mobility group box 1 (HMGB1) in inflammation is well characterized in the immune system and in response to tissue injury. More recently, HMGB1 was also shown to initiate an "inflammatory signaling cascade" in the brain parenchyma after a mild and brief disturbance, such as cortical spreading depolarization (CSD), leading to headache. Despite substantial evidence implying a role for inflammatory signaling in prevalent neuropsychiatric disorders such as migraine and depression, how HMGB1 is released from healthy neurons and how inflammatory signaling is initiated in the absence of apparent cell injury are not well characterized.

Cortical spreading depolarization-induced constriction of penetrating arteries can cause watershed ischemia: A potential mechanism for white matter lesions.

Periventricular white matter lesions (WMLs) are common MRI findings in migraine with aura (MA). Although hemodynamic disadvantages of vascular supply to this region create vulnerability, the pathophysiological mechanisms causing WMLs are unclear. We hypothesize that prolonged oligemia, a consequence of cortical spreading depolarization (CSD) underlying migraine aura, may lead to ischemia/hypoxia at hemodynamically vulnerable watershed zones fed by long penetrating arteries (PAs).

Cortical spreading depression can be triggered by sensory stimulation in primed wild type mouse brain: a mechanistic insight to migraine aura generation.

Background: Unlike the spontaneously appearing aura in migraineurs, experimentally, cortical spreading depression (CSD), the neurophysiological correlate of aura is induced by non-physiological stimuli. Consequently, neural mechanisms involved in spontaneous CSD generation, which may provide insight into how migraine starts in an otherwise healthy brain, remain largely unclear. We hypothesized that CSD can be physiologically induced by sensory stimulation in primed mouse brain.

Overview of extracellular vesicle characterization techniques and introduction to combined reflectance and fluorescence confocal microscopy to distinguish extracellular vesicle subpopulations.

Extracellular vesicles (EVs) are nanoparticles (30 to 1000 nm in diameter) surrounded by a lipid-bilayer which carry bioactive molecules between local and distal cells and participate in intercellular communication. Because of their small size and heterogenous nature they are challenging to characterize. Here, we discuss commonly used techniques that have been employed to yield information about EV size, concentration, mechanical properties, and protein content.

Confocal reflectance microscopy for metal and lipid nanoparticle visualization in the brain.

A requirement for nanoparticle (NP) research is visualization of particles within cells and tissues. Limitations of electron microscopy and low yields of NP fluorescent tagging warrant the identification of alternative imaging techniques. Confocal reflectance microscopy (CRM) in combination with fluorescence imaging was assessed for visualizing rhodamine B-conjugated silver and fluorescein isothiocyanate-conjugated lipid core-stearylamine NP uptake and .

Contractile apparatus in CNS capillary pericytes.

Whether or not capillary pericytes contribute to blood flow regulation in the brain and retina has long been debated. This was partly caused by failure of detecting the contractile protein -smooth muscle actin ( -SMA) in capillary pericytes. The aim of this review is to summarize recent developments in detecting -SMA and contractility in capillary pericytes and the relevant literature on the biology of actin filaments.

Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression.

Migraine and major depression are debilitating disorders with high lifetime prevalence rates. Interestingly these disorders are highly comorbid and show significant heritability, suggesting shared pathophysiological mechanisms. Non-homeostatic function of ion channels and neuroinflammation may be common mechanisms underlying both disorders: The excitation-inhibition balance of microcircuits and their modulation by monoaminergic systems, which depend on the expression and function of membrane located K, Na, and Ca channels, have been reported to be disturbed in both depression and migraine.

Parenchymal neuroinflammatory signaling and dural neurogenic inflammation in migraine.

Background: Pain is generally concomitant with an inflammatory reaction at the site where the nociceptive fibers are activated. Rodent studies suggest that a sterile meningeal inflammatory signaling cascade may play a role in migraine headache as well. Experimental studies also suggest that a parenchymal inflammatory signaling cascade may report the non-homeostatic conditions in brain to the meninges to induce headache.

Widespread brain parenchymal HMGB1 and NF-κB neuroinflammatory responses upon cortical spreading depolarization in familial hemiplegic migraine type 1 mice.

Neuroinflammatory changes involving neuronal HMGB1 release and astrocytic NF-κB nuclear translocation occur following cortical spreading depolarization (CSD) in wildtype (WT) mice but it is unknown to what extent this occurs in the migraine brain. We therefore investigated in familial hemiplegic migraine type 1 (FHM1) knock-in mice, which express an intrinsic hyperexcitability phenotype, the extent of neuroinflammation without and after CSD. CSD was evoked in one hemisphere by pinprick (single CSD) or topical KCl application (multiple CSDs).

Brain glycogen metabolism: A possible link between sleep disturbances, headache and depression.

The functions of sleep and its links with neuropsychiatric diseases have long been questioned. Among the numerous hypotheses on sleep function, early studies proposed that sleep helps to replenish glycogen stores consumed during waking. Later studies found increased brain glycogen after sleep deprivation, leading to "glycogenetic" hypothesis, which states that there is a parallel increase in synthesis and utilization of glycogen during wakefulness, whereas decrease in the excitatory transmission creates an imbalance causing accumulation of glycogen during sleep.

Pericyte morphology and function.

The proper delivery of blood is essential for healthy neuronal function. The anatomical substrate for this precise mechanism is the neurovascular unit, which is formed by neurons, glial cells, endothelia, smooth muscle cells, and pericytes. Based on their particular location on the vessel wall, morphology, and protein expression, pericytes have been proposed as cells capable of regulating capillary blood flow.

KCl-induced cortical spreading depression waves more heterogeneously propagate than optogenetically-induced waves in lissencephalic brain: an analysis with optical flow tools.

Although cortical spreading depolarizations (CSD) were originally assumed to be homogeneously and concentrically propagating waves, evidence obtained first in gyrencephalic brains and later in lissencephalic brains suggested a rather non-uniform propagation, shaped heterogeneously by factors like cortical region differences, vascular anatomy, wave recurrences and refractory periods. Understanding this heterogeneity is important to better evaluate the experimental models on the mechanistics of CSD and to make appropriate clinical estimations on neurological disorders like migraine, stroke, and traumatic brain injury. This study demonstrates the application of optical flow analysis tools for systematic and objective evaluation of spatiotemporal CSD propagation patterns in anesthetized mice and compares the propagation profile in different CSD induction models.

F-actin polymerization contributes to pericyte contractility in retinal capillaries.

Although it has been documented that central nervous system pericytes are able to contract in response to physiological, pharmacological or pathological stimuli, the underlying mechanism of pericyte contractility is incompletely understood especially in downstream pericytes that express low amounts of alpha-smooth muscle actin (α-SMA). To study whether pericyte contraction involves F-actin polymerization as in vascular smooth muscle cells, we increased retinal microvascular pericyte tonus by intravitreal injection of a vasoconstrictive agent, noradrenaline (NA). The contralateral eye of each mouse was used for vehicle injection.

Combination of Paclitaxel and R-flurbiprofen loaded PLGA nanoparticles suppresses glioblastoma growth on systemic administration.

Malignant gliomas are highly lethal. Delivering chemotherapeutic drugs to the brain in sufficient concentration is the major limitation in their treatment due to the blood-brain barrier (BBB). Drug delivery systems may overcome this limitation and can improve the transportation through the BBB.

Small Vessels Are a Big Problem in Neurodegeneration and Neuroprotection.

The cerebral microcirculation holds a critical position to match the high metabolic demand by neuronal activity. Functionally, microcirculation is virtually inseparable from other nervous system cells under both physiological and pathological conditions. For successful bench-to-bedside translation of neuroprotection research, the role of microcirculation in acute and chronic neurodegenerative disorders appears to be under-recognized, which may have contributed to clinical trial failures with some neuroprotectants.

Retinal ischemia induces α-SMA-mediated capillary pericyte contraction coincident with perivascular glycogen depletion.

Increasing evidence indicates that pericytes are vulnerable cells, playing pathophysiological roles in various neurodegenerative processes. Microvascular pericytes contract during cerebral and coronary ischemia and do not relax after re-opening of the occluded artery, causing incomplete reperfusion. However, the cellular mechanisms underlying ischemia-induced pericyte contraction, its delayed emergence, and whether it is pharmacologically reversible are unclear.

Pericytes in Ischemic Stroke.

Recent stroke research has shifted the focus to the microvasculature from neuron-centric views. It is increasingly recognized that a successful neuroprotection is not feasible without microvascular protection. On the other hand, recent studies on pericytes, long-neglected cells on microvessels have provided insight into the regulation of microcirculation.

The effect of carotid artery stenting on capillary transit time heterogeneity in patients with carotid artery stenosis.

Introduction: Carotid revascularisation improves haemodynamic compromise in cerebral circulation as an additional benefit to the primary goal of reducing future thromboembolic risk. We determined the effect of carotid artery stenting on cerebral perfusion and oxygenation using a perfusion-weighted MRI algorithm that is based on assessment of capillary transit-time heterogeneity together with other perfusion and metabolism-related metrics.

Patients And Methods: A consecutive series of 33 patients were evaluated by dynamic susceptibility contrast perfusion-weighted MRI prior to and within 24 h of the endovascular procedure.