Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • 2024-07
  • ml7 br Brain Angiotensin II receptors

    2024-07-09


    Brain Angiotensin II receptors The information above leaves Angiotensin II receptors as the only RAAS components for which localization, regulation of expression and function in the ml7 has been convincingly demonstrated, with the use of quantitative film and emulsion autoradiography to study receptor binding and in situ hybridization and qPCR to determine receptor gene expression, as reviewed elsewhere [26], [27], [28], [29]. Angiotensin AT1 receptors (AT1A and AT1B receptor subtypes in rodents but a single type in humans) [30] have been localized to multiple structures in the brain. Many studies revealed a physiological role of AT1 receptors in the regulation of the cerebral vasculature and therefore blood flow to the brain, the central and peripheral sympathetic system, hormone production and release, and behavior. The participation of AT1 receptors in multiple brain functions has been extensively reviewed elsewhere [26], [27], [28], [29], [31], [32], [33] . The discovery and use of AT1 receptor blockers raised the question of the relevance of AT2 receptor over stimulation by increased production of Angiotensin II [34]. While there is suggestive evidence of an interaction, probably indirect, between AT1 and AT2 receptors, the hypothesis of a major protective role by controlling AT1 receptor activity has been hotly disputed [35], and is still under investigation [26], [29], [33] .
    Evidence for shared mechanisms of injury linked to many brain disorders, including AT1 receptor over activity, and for the therapeutic effect of AT1 receptor blockade There is unambiguous evidence supporting the hypothesis that the initial injury mechanism leading to the development and progression of several brain disorders is dysfunction of the neurovascular unit and the cerebrovascular endothelium. The key pathogenic role of endothelial dysfunction in cardiovascular disorders has been firmly established [36], [37], and very similar mechanisms are involved in the development and progression of many brain disorders. Cerebrovascular endothelial cells are particularly vulnerable to age-dependent injury mechanisms accelerating their senescence process, and endothelial cell injury is a common early pathogenic mechanism for apparently very diverse conditions (Fig. 1). Factors involved in endothelial cell disease include increased inflammation and oxidative stress, alterations in the regulation of apoptosis, excitotoxic glutamate damage, mitochondrial dysfunction with impairment of the oxidative phosphorylation electron transport chain (Cx complexes) altering energy sensing protective pathways [29], [38], [39] . Cerebrovascular endothelial injury leads to blood-brain-barrier breakdown, leukocyte infiltration of the brain parenchyma and to a vicious circle of increased inflammation and oxidative damage [40]. These processes are associated with progressive deficiency of oxygen and nutrient supply to the brain parenchyma, cellular injury and loss of brain function (Fig. 1, Fig. 2). These key and very early pathogenic mechanisms have been extensively demonstrated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease as described below, and they possibly participate in several additional neurodegenerative disorders of the brain [40]. It has also been established that AT1 receptor over activity is a common feature of many brain disorders, and is a major initial event leading to endothelial dysfunction [29]. Uncontrolled AT1 stimulation produces and enhances associated mechanisms of cell injury, including increased brain inflammation and oxidative damage, alterations in mitochondrial function with disruption of the mitochondrial respiratory chain, cell injury because of glutamate excitotoxicity, reduction of cerebral blood flow leading to hypoxia and reduction of access to glucose and other essential nutrients (Fig. 3) [26], [27], [28], [29], [31], [32], [33]. A group of compounds, AT1 receptor blockers (ARBs) effectively reduce over activity of AT1 receptors in the periphery and the brain. The ARB group is heterogeneous, with some members, notably Telmisartan and to a lesser extent Candesartan, exhibiting a pleiotropic profile, not only blocking AT1 receptors but also activating peroxisome proliferator-activated receptor gamma (PPARγ), an anti-inflammatory, pro-metabolic nuclear receptor [29] (Fig. 4). The key role of increased AT1 receptor activation as an early, and perhaps fundamental injury factor in brain disorders (Fig. 3) is amply substantiated by the discovery that AT1 receptor blockade protects mitochondrial function in cerebrovascular endothelial cells exposed to oxidative stress and other early injury mechanisms as described above [29], [38], [39], [41] .