Luseogliflozin, a sodium-glucose co-transporter 2 inhibitor, reverses cerebrovascular dysfunction and cognitive impairments in 18-month-old diabetic animals

2021 ◽  
Author(s):  
Shaoxun Wang ◽  
Feng Jiao ◽  
Jane J. Border ◽  
Xing Fang ◽  
Reece F. Crumpler ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Plasma Glucose ◽  
Cognitive Impairments ◽  
Cerebral Arteries ◽  
Diabetic Rats ◽  
Age Related ◽  
Cerebrovascular Dysfunction ◽  
Middle Cerebral Arteries ◽  
Species Production ◽  
Hba1c Levels

Diabetes mellitus (DM) is a leading risk factor for age-related dementia, but the mechanisms involved remain to be elucidated. We previously discovered that hyperglycemia-induced impaired myogenic response (MR) and cerebral blood flow (CBF) autoregulation in 18-month-old DM rats associated with blood-brain barrier (BBB) leakage, impaired neurovascular coupling, and cognitive impairment. In the present study, we examined whether reduction of plasma glucose with a sodium-glucose co-transporter 2 inhibitor (SGLT2i) luseogliflozin can ameliorate cerebral vascular and cognitive function in diabetic rats. Plasma glucose and HbA1c levels of 18-month-old DM rats were reduced, and blood pressure was not altered after treatment with luseogliflozin. SGLT2i treatment restored the impaired MR of middle cerebral arteries (MCAs) and parenchymal arterioles, and surface and deep cortical CBF autoregulation in DM rats. Luseogliflozin treatment also rescued neurovascular uncoupling, reduced BBB leakage and cognitive deficits in DM rats. However, SGLT2i did not have direct constrictive effects on vascular smooth muscle cells and MCAs isolated from normal rats, although it decreased reactive oxygen species production in cerebral vessels of DM rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.

Effects of maturation on adrenergic neurotransmission in ovine cerebral arteries

1999 ◽  
Vol 277 (4) ◽  
pp. R931-R937 ◽  
Author(s):  
William J. Pearce ◽  
Sue P. Duckles ◽  
John Buchholz
Keyword(s):  
Cerebral Arteries ◽  
Age Groups ◽  
Peptidergic Neurons ◽  
Synaptic Density ◽  
Vasoactive Substances ◽  
Age Related ◽  
Middle Cerebral Arteries ◽  
Adrenergic Neurotransmission ◽  
Fractional Release ◽  
Two Age Groups

The present studies examine the hypothesis that multiple adrenergic neuroeffector mechanisms are not fully developed in fetal, compared with adult, ovine middle cerebral arteries. In arteries denuded of endothelium and pretreated with 1 μM atropine to block involvement of muscarinic receptors, 10 μM capsaicin to deplete sensory peptidergic neurons, and 10 μM nitro-l-arginine methyl ester (l-NAME) to block possible influences from nitric oxidergic innervation, transmural stimulation at 16 Hz increased contractile tensions to 9.5 ± 3.7% ( n = 6) of the potassium maximum in adult arteries. Corresponding values in fetal arteries, however, were significantly less and averaged only 1.1 ± 0.6% ( n =10). However, postsynaptic sensitivity to norepinephrine (NE) was similar in the two age groups; NE pD2 values (−log EC50) averaged 6.11 ± 0.12 ( n = 6) and 6.33 ± 0.09 M ( n = 9) in fetal and adult arteries, respectively. Similarly, NE content measured via HPLC was also similar in the two age groups and averaged 32.4 ± 5.0 ( n = 17) and 32.5 ± 3.9 ng/ng wet wt ( n = 13) in fetal and adult middle cerebral arteries, respectively. In contrast, stimulation-induced NE release was greater in fetal than in adult arteries, whether calculated as total mass released [883 ± 184 ( n = 17) vs. 416 ± 106 pg NE/mg wet wt ( n = 13)] or as fractional release [51.1 ± 5.3 ( n = 17) vs. 22.8 ± 3.8 pg/pg NE content per pulse × 10−6]. Measured as an index of synaptic density, neuronal cocaine-sensitive NE uptake was similar in fetal and adult arteries [1.55 ± 0.40 ( n = 10) and 1.84 ± 0.51 pmol/mg wet wt ( n = 7), respectively]. Overall, age-related differences in postsynaptic sensitivity to NE, NE release, and NE uptake capacity cannot explain the corresponding age-related differences in response to stimulation. The data thus suggest that total synaptic volume and cleft width, in particular, are probably greater and/or that adrenergic corelease of vasoactive substances other than NE is altered in fetal compared with adult middle cerebral arteries.

scholarly journals IGF-1 Deficiency Impairs Cerebral Myogenic Autoregulation in Hypertensive Mice

2014 ◽  
Vol 34 (12) ◽  
pp. 1887-1897 ◽  
Author(s):  
Peter Toth ◽  
Zsuzsanna Tucsek ◽  
Stefano Tarantini ◽  
Danuta Sosnowska ◽  
Tripti Gautam ◽  
...  
Keyword(s):  
Cerebral Arteries ◽  
Vascular Cognitive Impairment ◽  
Functional Adaptation ◽  
Trpc Channels ◽  
Cytokines And Chemokines ◽  
Age Related ◽  
Middle Cerebral Arteries ◽  
Chronic Infusion ◽  
The Brain ◽  
Deficient Mice

Aging impairs autoregulatory protection in the brain, exacerbating hypertension-induced cerebromicrovascular injury, neuroinflammation, and development of vascular cognitive impairment. Despite the importance of the age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels in cerebrovascular aging, the effects of IGF-1 deficiency on functional adaptation of cerebral arteries to high blood pressure remain elusive. To determine whether IGF-1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF-1-deficient mice ( Igf1 f/f+TBG-iCre-AAV8) by chronic infusion of angiotensin-II. In hypertensive control mice, cerebral blood flow (CBF) autoregulation was extended to higher pressure values and the pressure-induced tone of middle cerebral arteries (MCAs) was increased. In hypertensive IGF-1-deficient mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice, the mechanism of adaptation to hypertension involved upregulation of TRPC channels in MCAs and this mechanism was impaired in hypertensive IGF-1-deficient mice. Likely downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF-1-deficient mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF-1 deficiency impairs autoregulatory protection in the brain of hypertensive mice, potentially exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype.

Effects of maturation on alpha-adrenergic receptor affinity and occupancy in small cerebral arteries

1994 ◽  
Vol 267 (2) ◽  
pp. H757-H763 ◽  
Author(s):  
S. R. Elliott ◽  
W. J. Pearce
Keyword(s):  
Adrenergic Receptor ◽  
Cerebral Arteries ◽  
Receptor Occupancy ◽  
Stretch Ratio ◽  
Maximal Response ◽  
Receptor Affinity ◽  
Age Related ◽  
Middle Cerebral Arteries ◽  
Before And After ◽  
Norepinephrine Dose

The present experiments examine the hypothesis that changes in receptor affinity and occupation mediate maturational changes in norepinephrine sensitivity in small cerebral arteries. In second-order (2B) and fourth-order (4B) branch middle cerebral artery segments from newborn and adult sheep, we first found that a stretch ratio based on artery diameter better estimated optimal prestretch than did passive tension. Next, we determined norepinephrine dose-response relations before and after prazosin, yohimbine, and benextramine. Prazosin competitively blocked contractions to norepinephrine, but yohimbine had no effect, indicating that alpha 1-adrenoceptors mediated contraction. Norepinephrine sensitivity [determined from the -log of the half-maximal effective dose (pD2)], maximal response, and binding affinity all decreased with age in 4B but not 2B segments. Receptor occupancy at the pD2 increased with age only in 2B segments. In conclusion, maturation of ovine middle cerebral arteries involves branch-specific changes in affinity and receptor occupation of the alpha 1-adrenoceptors that mediate contractile responses to norepinephrine. Age-related changes in receptor density and/or intrinsic efficacy probably are involved also.

scholarly journals Dysfunction of Mouse Cerebral Arteries during Early Aging

2015 ◽  
Vol 35 (9) ◽  
pp. 1445-1453 ◽  
Author(s):  
Matilde Balbi ◽  
Mitrajit Ghosh ◽  
Thomas A Longden ◽  
Max Jativa Vega ◽  
Benno Gesierich ◽  
...  
Keyword(s):  
Cerebral Arteries ◽  
Brain Slices ◽  
Neurovascular Coupling ◽  
Global Changes ◽  
Cerebral Vessel ◽  
Pial Vessels ◽  
Age Related ◽  
Increased Risk ◽  
Cerebrovascular Dysfunction

Aging leads to a gradual decline in the fidelity of cerebral blood flow (CBF) responses to neuronal activation, resulting in an increased risk for stroke and dementia. However, it is currently unknown when age-related cerebrovascular dysfunction starts or which vascular components and functions are first affected. The aim of this study was to examine the function of microcirculation throughout aging in mice. Microcirculation was challenged by inhalation of 5% and 10% CO2 or by forepaw stimulation in 6-week, 8-month, and 12-month-old FVB/N mice. The resulting dilation of pial vessels and increase in CBF was measured by intravital fluorescence microscopy and laser Doppler fluxmetry, respectively. Neurovascular coupling and astrocytic endfoot Ca2+ were measured in acute brain slices from 18-month-old mice. We did not reveal any changes in CBF after CO2 reactivity up to an age of 12 months. However, direct visualization of pial vessels by in vivo microscopy showed a significant, age-dependent loss of CO2 reactivity starting at 8 months of age. At the same age neurovascular coupling was also significantly affected. These results suggest that aging does not affect cerebral vessel function simultaneously, but starts in pial microvessels months before global changes in CBF are detectable.

scholarly journals Roles of cytosolic Ca2+concentration and myofilament Ca2+sensitization in age-dependent cerebrovascular myogenic tone

2010 ◽  
Vol 299 (4) ◽  
pp. H1034-H1044 ◽  
Author(s):  
Shelton M. Charles ◽  
Lubo Zhang ◽  
Marilyn J. Cipolla ◽  
John N. Buchholz ◽  
William J. Pearce
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cerebral Arteries ◽  
Cyclopiazonic Acid ◽  
Muscle Cells ◽  
Myogenic Tone ◽  
Apparent Change ◽  
Age Related ◽  
Middle Cerebral Arteries ◽  
Age Dependent

In light of evidence that immature arteries contain a higher proportion of noncontractile smooth muscle cells than found in fully differentiated mature arteries, the present study explored the hypothesis that age-related differences in the smooth muscle phenotype contribute to age-related differences in contractility. Because Ca2+handling differs markedly between contractile and noncontractile smooth muscle, the present study specifically tested the hypothesis that the relative contributions of Ca2+influx and myofilament sensitization to myogenic tone are upregulated, whereas Ca2+release is downregulated, in immature [14 days postnatal (P14)] compared with mature (6 mo old) rat middle cerebral arteries (MCAs). Myofilament Ca2+sensitivity measured in β-escin-permeabilized arteries increased with pressure in P14 but not adult MCAs. Cyclopiazonic acid (an inhibitor of Ca2+release from the sarcoplasmic reticulum) increased diameter and reduced Ca2+in adult MCAs but increased diameter with no apparent change in Ca2+in P14 MCAs. La3+(Ca2+influx inhibitor) increased diameter and decreased Ca2+in adult MCAs, but in P14 MCAs, La3+increased diameter with no apparent change in Ca2+. After treatment with both La3+and CPA, diameters were passive in both adult and P14 MCAs, but Ca2+was decreased only in adult MCAs. To quantify the fraction of smooth muscle cells in the fully differentiated contractile phenotype, extents of colocalization between smooth muscle α-actin and SM2 myosin heavy chain were determined and found to be at least twofold greater in adult than pup MCAs. These data suggest that compared with adult MCAs, pup MCAs contain a greater proportion of noncontractile smooth muscle and, as a consequence, rely more on myofilament Ca2+sensitization and Ca2+influx to maintain myogenic reactivity. The inability of La3+to reduce cytosolic Ca2+in the pup MCA appears due to La3+-insensitive noncontractile smooth muscle cells, which contribute to the spatially averaged measurements of Ca2+but not contraction.

DIFFICULTIES IN DIAGNOSING MOYA-MOYA DISEASE (CLINICAL CASE)

2020 ◽  
pp. 48-53
Author(s):  
Novikova I.N. ◽  
Popova T.F. ◽  
Gribacheva I.A. ◽  
Petrova E.V. ◽  
Marushchak A.A. ◽  
...  
Keyword(s):  
Cerebral Angiography ◽  
Neurological Disorders ◽  
Clinical Case ◽  
Carotid Arteries ◽  
Internal Carotid ◽  
Cerebral Arteries ◽  
Moya Moya Disease ◽  
Middle Cerebral Arteries ◽  
Internal Carotid Arteries ◽  
Made In

Moya-Moya disease is a rare progressive chronic cer-ebrovascular disease characterized by a narrowing of the lumen of the intracranial segments of the internal carotid arteries, as well as the initial segments of the anterior and middle cerebral arteries with the devel-opment of a network of small vascular anastomoses. Violations of blood supply due to occlusion lead to the development of ischemic strokes in the correspond-ing pools, and ruptures of vascular anastomoses - to the development of hemorrhagic strokes, causing a variety of neurological disorders. The article presents a clinical case of Moya-Moya disease in a 31-year-old patient. The disease was manifested by acute disorders of cerebral circulation in ischemic and hemorrhagic types. The diagnosis was made in accordance with the diagnostic criteria of the disease based on the data of endovascular cerebral angiography.

Modulation of cerebral arterial tone by endothelium-derived relaxing factor

1993 ◽  
Vol 264 (4) ◽  
pp. H1245-H1250 ◽  
Author(s):  
J. E. Brian ◽  
R. H. Kennedy
Keyword(s):  
Nitric Oxide ◽  
Muscle Tone ◽  
Cerebral Arteries ◽  
Maximum Tension ◽  
Relaxing Factor ◽  
Middle Cerebral Arteries ◽  
Endothelium Derived Relaxing Factor ◽  
Vascular Smooth Muscle Tone ◽  
Dose Dependent ◽  
Arterial Tone

This study was designed to further elucidate the role of the endothelium in regulation of cerebral vascular smooth muscle tone. Dose-dependent vasoconstrictive effects of serotonin (5-HT) were examined in endothelium-intact and endothelium-denuded ring segments prepared from canine basilar and middle cerebral arteries. Some preparations were pretreated with 10(-5) M N omega-nitro-L-arginine (L-NNA), an agent that inhibits the production of L-arginine-derived nitric oxide, one of the compounds proposed to be endothelium-derived relaxing factor. L-NNA alone elicited marked dose-dependent increases in tension in endothelium-intact preparations; a significantly smaller response was seen in endothelium-denuded preparations. The effects of L-NNA on endothelium-intact preparations were partially reversed by washing and treatment with L-arginine. The maximum tension induced by 5-HT was approximately doubled by removal of the endothelium as well as by L-NNA treatment of endothelium-intact preparations; a slight increase in maximum tension occurred in endothelium-denuded preparations treated with L-NNA. The concentration of 5-HT producing half-maximal contraction (ED50) was not affected by L-NNA. These data suggest that L-arginine-derived nitric oxide modulates canine cerebral arterial tone in both the resting state and during contraction with 5-HT.

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