Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders - PubMed (original) (raw)
Review
Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders
Juan M Saavedra. Clin Sci (Lond). 2012 Nov.
Abstract
The effects of brain AngII (angiotensin II) depend on AT(1) receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT(1) receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood-brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT(1) receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT(1) receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer's disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer's disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic brain injury.
Figures
Figure 1. Central role of brain inflammation in brain disorders
When faced with environmental challenges, the brain attempts to maintain homoeostasis by adjusting its response to stress, regulating cerebrovascular flow and activating defensive inflammatory mechanisms. On a background of genetic vulnerability and over time, multiple environmental factors may enhance allostatic load. Loss of homoeostasis translates into pathological reactivity to stress, alterations in blood flow and uncontrolled inflammation. Excessive stress, brain trauma, cardiovascular disease, including hypertension and brain ischaemia, metabolic disorders, such as diabetes and obesity, and autoimmune processes contribute in variable degrees to the initiation and progression of brain disorders. The universal participation of excessive unregulated inflammatory processes is increasingly recognized. A vicious circle is established, with injured neurons contributing to further aseptic inflammation and progressive loss of function. The consequences are dependent on the systems involved and the different constellations of risk factors and include, to variable degrees, depression, impaired neurological performance and cognitive loss. Depending on the circumstances, the processes and mechanisms involved, the regulatory systems affected and the localization of neuronal injury, the loss of homoeostasis takes the form of one of multiple mood and degenerative disorders, which in turn further challenge homoeostatic mechanisms. Pathological disease mechanisms interact and this explains the high degree of co-morbidity between metabolic, cardiovascular, mood and neurodegenerative disorders.
Figure 2. Circulating pro-inflammatory factors and brain inflammatory cascades
Circulating inflammatory factors (bacterial endotoxins, pro-inflammatory cytokines, AngII, PGE2 and aldosterone) stimulate brain cerebrovascular endothelial target cells through activation of TLR4, cytokine receptors, AT1 receptors, PGE2 receptors (EP2 and EP4) and MRs respectively. The consequence is activation of intracellular inflammatory cascades with excessive production of PGE2, NO, pro-inflammatory cytokines, and adhesion molecules, and increased oxidative stress. Pro-inflammatory factors are released into the brain parenchyma, activating microglia and stimulating astrocytes, with further production of inflammatory cascades within the brain parenchyma. Blood–brain barrier breakdown allows macrophage infiltration into the brain parenchyma, increasing inflammation. Combinations of these factors result in neuronal injury. In turn, injured neurons produce danger signals with further microglia activation and astrocyte injury. When not adequately controlled, the continuous dialogue between peripheral and central inflammation leads to chronic inflammatory responses and permanent cell damage.
Figure 3. The RAS
The classical RAS includes the precursor angiotensinogen, the rate-limiting enzyme renin, forming the inactive peptide AngI, ACE producing the active peptide AngII, and the AT1 receptors responsible for the physiological and pathological effects of the RAS. RAS blockade may be achieved by decreasing AngII formation with ACEis or by directly antagonizing the effects of AngII with ARBs. Two balancing systems have been described: AT2 receptor stimulation by AngII, and Mas receptor activation by Ang-(1–7), produced by direct cleavage of AngII by ACE2, and by cleavage of AngI to yield Ang-(1–9), in turn converted into Ang-(1–7) by ACE. Neurotoxicity or neuroprotection has been proposed to depend on the interplay between AT1 receptor activation and AT2 and Mas receptor stimulation.
Figure 4. Physiological activation of AT1 receptors and the consequences of AT1 receptor overactivity
The physiological activation of AT1 receptors contributes to regulate the central sympathetic system, the HPA axis response, the peripheral cardiovascular system, the brain circulation, the brain and peripheral immune system, behaviour and cognition. In turn, overactivity of AT1 receptors is associated with stress-induced disorders, hypertension and vulnerability to ischaemia, excessive brain inflammation and autoimmune disorders, anxiety, depression and cognitive loss. Excessive AT1 receptor activity may be controlled by direct AT1 receptor blockade with ARBs.
Figure 5. TLR4 and AT1 receptors share common signal transduction mechanisms leading to inflammation
Stimulation of TLR4 and AT1 receptors in target cells up-regulates common pro-inflammatory mechanisms activating transcription factors, such as NF-κ_B, with the production of intracellular inflammatory cascades and increased oxidative stress. In addition, AT1 receptor stimulation inhibits the anti-inflammatory PPAR_γ system, indirectly activating NF-κ_B and other pro-inflammatory pathways. ARBs, also called sartans, act by inhibiting AT1 receptors to reduce inflammation and NF-κ_B activation directly or by removing AT1-receptor-mediated PPAR_γ inhibition, and, in some cases, by directly stimulating PPAR_γ.
Figure 6. Specific sartans display differential pharmacological profiles
Candesartan and most other sartans are imidazole derivatives containing a biphenyl-tetrazole group. Telmisartan is unique and does not contain the tetrazole group. Although both sartans share common class effects, such as AT1 receptor blockade, telmisartan activates PPAR_γ_ more effectively than candesartan. The AT1 receptor and PPAR_γ_ systems interact, with AT1 receptor stimulation decreasing PPAR_γ_ activity and PPAR_γ_ activation reducing AT1 receptor stimulation. This inverse balance between AT1 receptor stimulation and PPAR_γ_ activation indicates that the effects of ARBs on PPAR_γ_ may not be necessarily independent of AT1 receptor blockade.
References
- Nimmo AJ, Vink R. Recent patents in CNS drug discovery: the management of inflammation in the central nervous system. Recent Pat CNS Drug Discovery. 2009;4:86–95. - PubMed
- Zanchetti A, Elmfeldt D. Findings and implications of the Study on Cognition and Prognosis in the Elderly (SCOPE): a review. Blood Pressure. 2006;15:71–79. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials