Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide

Background Communication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and l-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have hitherto not been studied. Results Here, we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner. Conclusion Our findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function.

Impact of body mass index on duplex parameters of cranial vessels among the Egyptian population

Background Obesity is a major health problem that affects different vascular systems, including cerebrovascular circulation. Carotid duplex is the best screening tool for early diagnosis of cerebrovascular changes in relation to different risk factors including obesity. The present study aims to evaluate the effect of body mass index on the parameters of extracranial vessels in healthy subjects using vascular duplex ultrasonography. Results The intimal medial thickness in the common carotid is found to increase as the body mass index and body weight increase (directly related), with this increase being significant (P-value < 0.05). Conclusion These findings indicate that increase in body mass index can adversely affect duplex parameters of the common carotid artery. Clinical trial registration NCT03252652. Registered August 16th 2017

State of proteolytic and fibrinolytic processes in the brain of rats with experimental diabetes mellitus complicated by cerebrovascular accident in the basin of the carotid arteries

Introduction. The imbalance in the protease-antiprotease system is an integral part of the pathogenesis of acute disorder of cerebrovascular circulation and diabetes mellitus (DM), but its manifestations in the complication of diabetes by ischemia-reperfusion of the brain have not been investigated yet. The objective of the work – to study the dynamics of carotid ischemia-reperfusion effect on the proteo- and fibrinolytic activity in brain structures of rats with experimental DM. Rats with the four-month streptozotocin DM were modeled bilateral carotene ischemia during 20 minutes. In homogenates of brain structures, indicators of proteo- fibrinolytic activity were determined after 1 hour from the beginning of reperfusion and during the 12th day of the post-ischemic period. In the absence of DM, the proteolytic activity of all or individual indicators il increased in both periods of the post-ischemic period in the cortex of the frontal and occipital lobes, the fields of hippocampus CA2 and CA3, and during the 12th day in the field CA1. Results. In rats with diabetes, in all brain structures, there are no changes in the lysis of azo-albumin and azo-casein in both terms of observation and lysis of collagen progressively decreases. In rats without DM in the cortex of the studied particles, fields of the hippocampus CA1 and CA2, all or separate indices of fibrinolytic activity are increased in both periods of the post-ischemic period, in the field CA3 – all indices at the 12th day. In the presence of diabetes in the cortex of both studied lobes and the field CA1, the fibrinolytic activity decreases in the late post-ischemic period, in the fields of CA2 and CA3 – during both observation periods. Conclusion. In the brain structures under investigation at both time intervals, the DM eliminates the reaction of low and high molecular weight proteins to the ischemia-reperfusion and suppresses fibrinolytic activity.

Integrative cerebral blood flow regulation in ischemic stroke

Optimizing cerebral perfusion is key to rescuing salvageable ischemic brain tissue. Despite being an important determinant of cerebral perfusion, there are no effective guidelines for blood pressure (BP) management in acute stroke. The control of cerebral blood flow (CBF) involves a myriad of complex pathways which are largely unaccounted for in stroke management. Due to its unique anatomy and physiology, the cerebrovascular circulation is often treated as a stand-alone system rather than an integral component of the cardiovascular system. In order to optimize the strategies for BP management in acute ischemic stroke, a critical reappraisal of the mechanisms involved in CBF control is needed. In this review, we highlight the important role of collateral circulation and re-examine the pathophysiology of CBF control, namely the determinants of cerebral perfusion pressure gradient and resistance, in the context of stroke. Finally, we summarize the state of our knowledge regarding cardiovascular and cerebrovascular interaction and explore some potential avenues for future research in ischemic stroke.

Regulation of blood–brain barrier integrity and cognition by the microbiome-associated methylamines trimethylamine-N-oxide and trimethylamine

ABSTRACTCommunication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and L-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have not hitherto been studied. Here we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N- oxide (TMAO) enhanced and protected blood-brain barrier (BBB) integrity, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO has beneficial effects upon cognition in mice, improving visual recognition memory. Our findings demonstrate a direct interaction of microbiome-associated metabolites with the mammalian BBB, with consequences for cerebrovascular and cognitive function.

The Potential Role of Hydrogen Sulfide in the Regulation of Cerebrovascular Tone

A better understanding of the regulation of cerebrovascular circulation is of great importance because stroke and other cerebrovascular diseases represent a major concern in healthcare leading to millions of deaths yearly. The circulation of the central nervous system is regulated in a highly complex manner involving many local factors and hydrogen sulfide (H2S) is emerging as one such possible factor. Several lines of evidence support that H2S takes part in the regulation of vascular tone. Examinations using either exogenous treatment with H2S donor molecules or alterations to the enzymes that are endogenously producing this molecule revealed numerous important findings about its physiological and pathophysiological role. The great majority of these studies were performed on vessel segments derived from the systemic circulation but there are important observations made using cerebral vessels as well. The findings of these experimental works indicate that H2S is having a complex, pleiotropic effect on the vascular wall not only in the systemic circulation but in the cerebrovascular region as well. In this review, we summarize the most important experimental findings related to the potential role of H2S in the cerebral circulation.

Dynamics of Proteo- and Fibrinolytic Activity in Brain Structures of Rats with Diabetes Mellitus Complicated by Carotid Ischemia-Reperfusion

The imbalance in the protease-antiprotease system is an integral part of the pathogenesis of acute disorder of cerebrovascular circulation and diabetes mellitus (DM), but its manifestations in the complication of diabetes by ischemia-reperfusion of the brain have not been investigated yet.The objective of the work – is to study the dynamics of carotid ischemia-reperfusion effect on the proteo- and fibrinolytic activity in brain structures of rats with experimental DM.Rats with the four-month streptozotocin DM were modeled bilateral carotene ischemia during 20 minutes. In homogenates of brain structures, indicators of proteo- fibrinolytic activity were determined after 1 hour from the beginning of reperfusion and during the 12th day of the post-ischemic period.In the absence of DM, the proteolytic activity of all or individual indicators is increased in both periods of the post-ischemic period in the cortex of the frontal and occipital lobes, the fields of hippocampus CA2 and CA3, and during the 12th day in the field CA1. In rats with diabetes, in all brain structures, there are no changes in the lysis of azo-albumin and azo-casein in both terms of observation and lysis of collagen progressively decreases.In rats without DM in the cortex of the studied particles, fields of the hippocampus CA1 and CA2, all or separate indices of fibrinolytic activity are increased in both periods of the post-ischemic period, in the field CA3 – all indices at the 12th day. In the presence of diabetes in the cortex of both studied lobes and the field CA1, the fibrinolytic activity decreases in the late post-ischemic period, in the fields of CA2 and CA3 – during both observation periods.Conclusion. In the brain structures under investigation at both time intervals, the DM eliminates the reaction of low and high molecular weight proteins to the ischemia-reperfusion and suppresses fibrinolytic activity.

Preparation and Regeneration of Protoplasts from the Ethyl Vincamine Producing Fungus CH1 (Geomyces sp.)

Vinpocetine, a semi-synthetic compound derived from the alkaloid vincamine, exhibits effective pharmacological activities for the treatment and prevention of cerebrovascular circulation and vascular cognitive disorders. Vinpocetine can be produced through a one-step chemical reaction beginning with ethyl vincamine, and a two-step chemical reaction beginning with vincamine. In our previous study, the endophytic fungus CH1, Geomyces sp., was isolated and identified as a producer of ethyl vincamine, which was first obtained by endophytic fungal fermentation. However, the production was largely limited. Fungal protoplasts are a valuable experimental tool for physiological and genetic research such as protoplast fusion, gene transfer and metabolite production. In this paper, we optimized some key factors for the preparation and regeneration of protoplasts from strain CH1. Using an enzymes mixture consisting of cellulase (2.0%, w/v), glusulase (3.0%, w/v) and driselase (1.0%, w/v) in osmotic stabilizer (0.7 mol/L NaCl), the highest yield of protoplasts (6.78×107/mL) was obtained with mycelia after 72 h at pH 5.0-6.0 by digesting for 1.5 h at 30°C. After purification of the prepared protoplasts, they were regenerated in the regeneration medium using a bilayer plate culture method.

Abstract 21: Remote Limb Ischemic Postconditioning Improves Postresuscitation Cerebrovascular Circulation and Survival/Neurological Prognoses via In Situ and Remote Activation of Akt-eNOS-NO Signaling Pathway

Introduction: Cerebrovascular circulation is usually compromised after cardiac arrest and CPR. Remote limb ischemic post-conditioning (RLIP) is clinically feasible and can potentially mitigate post-resuscitation neurological deficits. Since nitric oxide (NO) is implicated in post-conditioning protection, we aim to investigate if RLIP impacts post-resuscitation cerebral perfusion and prognosis via NO-related mechanism. Hypothesis: RLIP improves post-CPR cerebral perfusion and prognosis through in situ and remote activation of Akt-eNOS-NO signaling. Methods: Using an established rat model of asphyxia cardiac arrest and CPR, we randomized the rats to the following groups: (1) sham, (2) standard CPR, (3) RLIP 5 min after return of spontaneous circulation (ROSC). RLIP was done by 3 cycles of 5 min of left hind limb ischemia followed by 5 min of reperfusion. Arterial blood was sampled for colorimetric determination of nitrate/nitrite. The cerebral perfusion was continuously recorded by OxyFLO probe. Two hours after ROSC, the brain and left femoral artery were harvested for measuring phosphorylated endothelial NO synthase (p-eNOS at Ser1177) and protein kinase B (p-Akt at Ser473). In a subgroup the survival and neurological outcomes were monitored up to 3 days. Results: The cerebral perfusion was significantly decreased (0.6-0.8 folds that of baseline) after ROSC in standard CPR group. If RLIP was employed, the cerebral perfusion was significantly augmented (up to 1.6 folds, P < 0.001) in the post-resuscitation phase. This was associated with improved survival (log-rank P < 0.05) and neurological scores at 6, 24, 48 and 72 h (all P < 0.05). Plasma NO as indicated by nitrate/nitrite was significantly increased in the RLIP group ( P < 0.05). Most of all, p-eNOS and p-Akt were significantly increased not only in left femoral artery but also in brain. If NOS inhibitor N ω -nitro-L-arginine methyl ester (10 mg/kg) was used, not only the NO increase was reversed, the improvement in survival and neurological outcomes were also abrogated. Conclusions: RLIP enhances post-resuscitation cerebral perfusion and improves survival and neurological prognoses not only via in situ limb artery derived NO but remote activation of Akt-eNOS signaling in the brain.

Vascular dementia: a pragmatic review

SummaryVascular dementia is associated with a group of diverse pathologies affecting the cerebrovascular circulation and with other dementia pathologies, particularly Alzheimer's disease. It is rather rare on its own. There is a spectrum of severity of cerebrovascular disease ranging from pathology but no cognitive impairment, to mild cognitive impairment to a dementia syndrome (vascular dementia). Where present, cerebrovascular disease can magnify the impact of other pathologies such as Alzheimer's disease. Current criteria for diagnosing vascular dementia are inadequate. Neuroimaging can be very helpful in defining the extent of pathology. Assessment needs to take into account a wide range of issues. Specific evidence-based treatments are limited, but attention should be given to managing risk factors and associated psychiatric problems such as depression.