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  • Writer's pictureGraham Exelby

Potential Role for use of Candesartan and Telmisartan in Mitigating Cognitive Impairment in Long COVID

Dr Graham Exelby May 2024


 

In 2020 a study involved the addition of candesartan to standard care for COVID-19 patients.  This found candesartan significantly reduced the length of hospital stay and improved primary outcomes in the non-obese group, although it did not address Long Covid or cognitive impairment (1)   I am unable to find any evidence of its continued use other than this study.

 

We hypothesize that in medication that should be considered in any treatment regime for Long Covid cognitive impairment,  the 2 anti-hypertensives Candesartan and Telmisartan should be considered, and there is a strong case for their use, although not approved by the TGA.   The complex processes involved, and the long-standing research in these 2 medications are described below.  

 

Hypothesis:


That both candesartan and telmisartan should improve post covid cognitive impairment.

Co-morbidities are so important in assessing the Long Covid patient.    Migraine, Alzheimers Disease, stroke, traumatic brain jury and telomerase are considered individually with reference to these medications.  


Candesartan and Telmisartan

  • Anti-inflammatory effects with neuroprotective qualities - both medication block angiotensin 11 type 1 receptor (AT1R).   The neuroprotective effects are mediated in part through their ability to regulate glutamate levels and signalling, thereby preventing excitotoxicity and oxidative damage to neurons via a modulation of the AT1-R signalling (2)   In animal studies, there is improved cognitive function.  Through blockade of the AT1 receptor, reduced neuronal death and enhanced neurogenesis, potentially beneficial in post-COVID cognitive recovery.

  • Modulation of the renin-angiotensin system (RAS,) a significant component in ischaemic stroke

  • Ability to cross the BBB- in both medications, this characteristic is crucial to allow them to exert direct effects on the brain, where they may prevent neuroinflammation and neuronal damage 

  • Both can modulate microglial and astrocyte dysfunction

  • Improved glutamate regulation, protecting neurons by decreasing excitotoxic glutamate release immediately after reperfusion following an ischaemic insult. (2)   Candesartan and telmisartan were shown to avert glutamate-induced neuronal death and genetic analyses indicated that the drug also prevented neuronal inflammation and a variety of other pathological processes associated with Alzheimer’s disease, including amyloid metabolism.(3)

  • Candesartan has been shown to inhibit the expression and activity of TLR2 both in vivo and in vitro.(4)  There is no information on the use of telmisartan on this.

  • Alzheimer's disease pathology is associated with brain inflammation involving microglia and astrocytes. The renin‐angiotensin system contributes to brain inflammation associated with AD pathology.  Telmisartan and candesartan modulate glial activation, significantly decreased the production of inflammatory mediators like nitric oxide, TNF-α, and IL-1β in response to lipopolysaccharide stimulation (5)(6)

  • Potential effect on telomerase

 

Traumatic Brain Injury and comparative efficacy


Traumatic brain injury results in neuronal injury and death, acute and prolonged inflammation and decreased blood flow.  ARBs that block angiotensin II type 1 receptors (AT1R, encoded by AGTR1) are strongly neuroprotective, neurorestorative and anti-inflammatory.     Mechanistically, their data indicate that ARB treatment affects two different signalling pathways to produce an improvement in recovery from traumatic brain injury, AT1R blockade and PPARγ activation.


Both candesartan and telmisartan ameliorated controlled cortical impact-induced injury with a therapeutic window up to 6 hr at doses that did not affect blood pressure. Both drugs decreased lesion volume, neuronal injury and apoptosis, astrogliosis, microglial activation, pro-inflammatory signalling, and protected cerebral blood flow, when determined 1 to 3 days post-injury. Both ARBs showed efficacy when administered up to 6 h post-injury. This time window allows for realistic clinical application. (7)


Controlled cortical impact-induced cognitive impairment was ameliorated 30 days after injury only by candesartan. The neurorestorative effects of candesartan and telmisartan were reduced by concomitant administration of the peroxisome proliferator-activated receptor gamma (PPARγ, encoded by PPARG) antagonist T0070907, showing the importance of PPARγ activation for the neurorestorative effect of these ARBs.(7)

 

Circulating endothelial progenitor cells (EPCs) provide an endogenous repair mechanism of the dysfunctional endothelium and therefore can play a crucial role in the pathophysiology of coronary artery disease (CAD).   Telmisartan increases the number of regenerative EPCs and improves endothelial function in normotensive patients with CAD.   Telmisartan has beneficial cardiovascular effects independent of its blood pressure lowering action. (8)


Villapol et al (7) used the lowest effective dose of each drug; 0.1 mg/kg candesartan and 1 mg/kg telmisartan, improving functional and morphological recovery after traumatic brain injury, with beneficial effects including acute and long-term reduction of lesion volume, enhancement of cognitive and motor function, protection of cerebral blood flow, and reduction in inflammation and the amount of activated microglia and astrocytes.   


For both candesartan and telmisartan, effects occur at non-hypotensive doses.   This effect correlated with a significant reduction in lesion volume that led to conservation of the majority of the hippocampus, an area of the brain associated with spatial working memory.   Although both drugs have somewhat similar effects initially, candesartan’s actions seem more beneficial at more chronic time points, suggesting that candesartan has better long-term benefit.


Administration of ARBs also protects the endothelium through inducing eNOS (encoded by Nos3) expression and reducing the expression of iNOS.   Thus, ARB treatment, by blockade of the AT1R, may protect the cerebrovasculature through numerous mechanisms after injury.(7)


There were also differential effects of the ARBs on functional recovery. Telmisartan, but not candesartan, partially improved motor function.   However, telmisartan’s benefit to functional recovery was restricted to this early time point.    Given that candesartan administration improved cognitive function up to 1 month after injury, it was surprising that candesartan administered after injury did not have more of an effect on motor function.

 

However, candesartan administration before injury improved motor performance.  At 30 days post-injury mice treated with candesartan showed improved function in a test of learning and spatial memory.   Although this protection of brain parenchyma could explain the improvement in cognitive function, there is also evidence that interfering with the brain’s RAS is beneficial to learning and memory. (9)


Individual ARBs have different pharmacological profiles. Telmisartan, in addition to its AT1R blocking properties, is a very effective partial PPARγ activator.  Candesartan has little PPARγ activating effects in cell culture systems, but is an effective PPARγ activator when administered in vivo.


Candesartan has a higher binding potency to the AT1R, and a slower dissociation than telmisartan, suggesting that it might be a better AT1R antagonist, even if a worse PPARγ agonist.  Telmisartan had slightly better short-term benefits, but by 1 month after injury, effects were significantly less than those of candesartan.


Thus, it is possible that at more acute time points, the stronger PPARγ agonist has greater benefit, but as the injury progresses, the importance of AT1R blockade is more prominent.


Stroke:

Telmisartan has been shown to improve cerebral circulation in hypertensive patients with chronic stroke. (7)  Telmisartan therapy had a sufficient hypotensive action on hypertensive patients with chronic-stage stroke, but cerebral blood flows were maintained in the cerebral hemispheres and did not decline, even on the infarct side.   Examination of cerebral blood flow by region also indicated increases in most regions. The mechanism behind this sustained cerebral blood flow despite the decline in BP is thought to involve the PPARγ agonist action of telmisartan, as well as its effects as an ARB. 


The angiotensin II receptor-blocking effects of telmisartan include its action on autoregulation of cerebral circulation. This autoregulation function is known to shift rightwards in hypertensive patients. It has been suggested that, in hypertensive animal models, telmisartan causes a leftward shift in the autoregulation curve similar to that of candesartan, thus enabling cerebral blood flow to be maintained even in a hypotensive state.


An additional mechanism of telmisartan is its effect on the vascular endothelium. A study of hypertensive rats by Saavedra et al. (10) found that blockade of AT1 receptors increases expression of AT2 receptors, leading to enhanced endothelial nitric oxide synthase activity and nitric oxide production in vascular endothelium.


Migraine

Candesartan's efficacy in migraine prophylaxis is an intriguing example of a cardiovascular medication repurposed for a neurological indication. The action of candesartan in migraine prevention is not fully understood but is believed to involve several mechanisms related to its primary pharmacological role as an angiotensin II receptor blocker (ARB).

 

The proposed mechanisms of action include:


  • Modulation of CNS excitability and sensitization pathways, independent of blood pressure effects

  • Preservation of BBB integrity

  • Neuronal protection by reducing oxidative stress caused by overactivation of angiotensin 11 in the brain

  • Modulation of glutamate-induced neural excitotoxicity - ARBs are neuroprotective, significantly reducing glutamate-induced neuronal injury and apoptosis.(20)  

  • Inhibition of cortical spreading depression (11)

  • Reduction in circulating levels of calcitonin gene-related peptide (CGRP), a neuropeptide strongly implicated in migraine.   

  • Candesartan may indirectly reduce CGRP release as angiotensin 11 can induce CGRP release. CGRP causes vasodilatation of cranial blood vessels, so candesartan may prevent or reduce the vasodilatation associated with migraine

 

Angiotensin II is a potent vasoactive peptide that plays a critical role in cardiovascular homeostasis, including blood pressure regulation and vascular tone. It exerts its effects primarily through the angiotensin II type 1 receptor (AT1). Beyond its vascular actions, angiotensin II has been implicated in various neurological processes, including pain signalling and inflammation, which are relevant to migraine pathophysiology.

 

Candesartan blocks the AT1 receptor, which can lead to vasodilation. While the role of vascular changes in migraine is complex and somewhat controversial, modulation of cerebral blood flow may alleviate the vascular dysregulation observed in migraine sufferers.

 

Angiotensin II is known to promote inflammation, a process that contributes to the pathogenesis of migraine. By blocking AT1 receptors, candesartan could reduce neuroinflammation, thereby decreasing the frequency or severity of migraine attacks.

 

There is evidence to suggest that ARBs, including candesartan, have neuroprotective properties. These effects might be mediated through the prevention of neuronal inflammation and oxidative stress, potentially mitigating the central sensitization observed in migraine patients.

 

Candesartan may influence central pain pathways, possibly through effects on neurotransmitter systems involved in pain perception. The exact mechanisms remain an area of ongoing research but could involve modulation of the renin-angiotensin system (RAS) components within the brain.

 

Telmisartan clinical trials for migraine prevention are limited compared to those for candesartan. This is partly due to the broader interest in candesartan based on its earlier identification as potentially beneficial for migraine sufferers. However, the unique properties of telmisartan, such as its longer half-life and PPAR-γ agonistic activity, provide a theoretical basis for its efficacy in migraine prevention.

 

Telmisartan's potential in migraine prophylaxis may derive from its ability to modulate vascular tone, reduce inflammation, and possibly affect metabolic pathways through PPAR-γ activation. These mechanisms could theoretically contribute to reducing the frequency or severity of migraine attacks, similar to how other ARBs are thought to function.

 

The linking with the glymphatic dysfunction caused by cortical spreading depression provides an interesting possibility for ARBs in controlling the dysfunctional glymphatic system.

 

Intracranial Hypertension and Intracranial Vascular Hypertension- Brain Spect findings

 

The ongoing POTS research has found these to be major parts of the symptomatology.  It is not uncommon to see peripheral hypotension accompanying symptoms highly suggestive of intracranial vascular hypertension, often accompanying symptoms of Intracranial Hypertension.   This is described full in the POTS articles.

 

Many of these patients have hyperperfused brain spects, reflecting increased blood flow/metabolic hyperfunction with accompanying endotheleiitis and BBB dysfunction.     Around 50% have co-existing brainstem hypoperfusion, an observation seen more commonly in CFS.


These Spect findings highlights a complex interplay between Intracranial Hypertension and craniovascular pressure dynamics, and the glymphatic’s role in maintaining cerebral homeostasis.   This functional waste clearance pathway uses the perivascular space to facilitate the flow of CFS around the brain’s vascular system. 


The clearance relies on the pressure gradients between the CSF and interstitial fluid, and the system’s efficiency is closely tied to the overall vascular health of the brain, and also to the other mechanical and inflammatory components seen in Long Covid.   Any imbalance in this system can impair the clearance function leading to the accumulation of neurotoxic substances and their contribution to neurological symptoms.


The hypothesis extends to assessing the role of the ERBs candesartan and telmisartan in improving the cerebral homeostasis.


Telomerase Connection

Telomerase is an enzyme complex capable of elongating telomeres, which are protective structures at the ends of chromosomes that shorten with each cell division. Telomere length is considered a marker of cellular aging, and its maintenance is crucial for cellular longevity and the prevention of senescence.  In most somatic cells, telomerase activity is low or absent, leading to progressive telomere shortening with each cell division. 

 

Both telmisartan and candesartan work by blocking the angiotensin II type 1 receptor (AT1R), reducing the effects of angiotensin II, a peptide hormone involved in blood pressure regulation and inflammation. Beyond their cardiovascular effects, there is interest in whether these ARBs might also influence telomerase activity and telomere length, potentially offering insights into their roles in cellular aging and age-related diseases. 

 

Preliminary studies have suggested that ARBs, including telmisartan and possibly candesartan, may have a positive effect on telomerase activity. For instance, some research indicates that telmisartan can enhance telomerase activity in endothelial cells, which could contribute to vascular health by promoting endothelial repair and reducing atherosclerotic changes. 

 

Angiotensin 11-mediated oxidative stress has been shown to accelerate aging by telomere attrition. (12)  There are studies that suggest the angiotensin!! Inhibition by candesartan and telmisartan could theoretically reduce oxidative stress and slow the rate of telomere shortening.

 

The mechanism might involve the activation of protective pathways beyond the blockade of AT1R, such as through PPAR-γ (peroxisome proliferator-activated receptor gamma) activation by telmisartan, which is unique among ARBs.   PPAR-γ is involved in the regulation of oxidative stress and inflammation, both of which are linked to telomere shortening.

 

Other areas demonstrating telmisartan effects on cellular functions include:

  • Telmisartan mitigating TNFα-induced degradation of type 11 collagen and upregulation of SOX-2 in chondrocytes, providing a promising agent in OA.(13)

  • Enhancing mitochondrial activity and altering cellular functions in human coronary artery endothelial cells via the AMPK pathway.(14)

  • Inducing proliferation of human endothelial progenitor cells via the PPAR-γ-dependent P13K/Akt pathway, contributing to endothelial integrity and vasculogenesis in ischaemia regions by increasing numbers of endothelial progenitor cells (15)

  • Aging of endothelial cells is hallmarked by a reduction in nitric oxide (NO) synthesis.  Telmisartan’s effect on the nitric oxide-asymmetrical dimethylarginine system increases NO synthesis.(16)

 

The potential implications of this are:

 

  • Cardiovascular protection: if telmisartan and candesartan can enhance telomerase activity in cardiovascular tissues, they might offer additional protection against cardiovascular aging by maintaining telomere length in vascular cells. This could reduce the risk of atherosclerosis, hypertension-related damage, and other age-related cardiovascular diseases.

  • Neuroprotection and Cognitive Function: Enhanced telomerase activity could also have implications for neuroprotection, potentially contributing to the maintenance of telomere length in neuronal cells. This might offer a mechanism for the neuroprotective effects observed with these ARBs, possibly impacting age-related cognitive decline and neurodegenerative diseases

  • Anti-inflammatory Effects: Given the role of inflammation in telomere shortening and cellular aging, the anti-inflammatory effects of ARBs could indirectly support telomere maintenance by reducing cellular stress and damage. This could slow the rate of telomere shortening over time, contributing to cellular longevity

  • Implications for Longevity: Enhancing telomerase activity and maintaining telomere length could have broader implications for aging and longevity. By potentially slowing down the cellular aging process, ARBs like telmisartan and candesartan could contribute to a reduced incidence of age-related diseases, including certain cancers, though this remains speculative and requires careful consideration given the complex role of telomerase in oncogenesis

 

Comparative Analysis

 

In summary, while both ARBs have plausible mechanisms suggesting potential benefits for post-COVID cognitive impairment, telmisartan's unique pharmacological properties might render it the more promising candidate for further investigation in this context.

 

Nonetheless, rigorous clinical research is required to substantiate these theoretical advantages and to optimize therapeutic strategies for post-COVID cognitive impairment.

 

Both improved glymphatic flow indirectly by reducing neuro-inflammation and promoting a neuroprotective microglial state.  Both are angiotensin 11 blockers which have been shown to improve cerebral perfusion and potentially improve glymphatic function.   By modulating the RAS they may optimize fluid dynamics and clearance mechanisms of the glymphatic system. (7)

 

Candesartan reduced amyloid-beta and modulated microglial polarization towards a more protective phenotype in mouse models, suggesting it may improve glymphatic clearance of harmful proteins eg amyloid-beta.(5)

 

Similarly telmisartan modulates macrophage/microglial polarization in different tissues.  In Parkinson’s Disease models, telmisartan protected dopaminergic neurons, reduced motor deficits, and inhibited microglial activation suggesting it may also have beneficial effects on glymphatic function by reducing neuroinflammation and promoting a neuroprotective microglial state.(6)

 

Candesartan has been shown to inhibit the expression and activity of TLR2 both in vivo and in vitro.(4) 

 

While both candesartan and telmisartan have mechanisms that could theoretically support their use in improving post-COVID cognitive impairment, telmisartan's additional PPAR-γ agonistic activity and superior BBB penetration may offer broader neuroprotective benefits. These include enhanced anti-inflammatory and antioxidant actions within the CNS, potentially improving cognitive outcomes more effectively than candesartan. (17)  However, it's important to note that the clinical efficacy of these theoretical benefits in the context of post-COVID cognitive impairment remains to be fully established.

 

Candesartan can improve arterial stiffness, an indicator of vascular health, which could indirectly enhance cerebral perfusion.    This improved arterial stiffness is independent of blood pressure lowering and without PPAR-γ agonist action, probably by direct action from its potent affinity and binding capacity for the angiotensin II type 1 receptor. (18)

 

Telmisartan, while sharing the AT1 receptor blockade mechanism, exhibits additional properties that might confer advantages in the context of cognitive impairment.  

 

  • PPAR-γ Inhibition: Unlike other ARBs, telmisartan acts as a partial agonist of the peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor involved in the regulation of insulin sensitivity, adipocyte differentiation, inflammation and endothelial function. This unique action may offer neuroprotective benefits beyond those related to angiotensin II blockade, particularly in metabolic regulation and neuroinflammation reduction.

  • Lipophilicity: Telmisartan's high lipophilicity allows for better penetration across the BBB, potentially enhancing its neuroprotective effects directly within the central nervous system (CNS).

  • Telmisartan is associated with lower risk of Alzheimer's disease (AD) in African Americans, but not other ARBs.   Telmisartan is the only angiotensin II receptor blockers having PPAR-γ agonistic properties with beneficial anti-diabetic and renal function effects, which mitigate AD risk in African Americans. (19)

 

Pharmokinetic Differences:

 

Half-Life: Telmisartan has a longer half-life compared to candesartan (24 hours vs. 9-12 hours), which might influence dosing frequency and the stability of their therapeutic effects. For cognitive impairments, a stable therapeutic effect could be advantageous, potentially making telmisartan a preferable option for sustained benefits

 

Clearance: Candesartan is primarily eliminated by both biliary and renal routes, whereas telmisartan is predominantly eliminated by the hepatic route. This distinction is particularly relevant in patients with renal or hepatic impairment, which could be present in those with severe COVID-19 histories.

 

Potential Problems:

 

1.     Renal and hepatic impairment: Given their modes of elimination, renal or hepatic dysfunction could alter the pharmacokinetics of candesartan and telmisartan, necessitating dose adjustments or careful monitoring to avoid toxicity

2.     Drug Interactions: The metabolic pathways of telmisartan (hepatic clearance primarily through CYP2C9) might intersect with those of other medications metabolized by the liver, raising the potential for drug-drug interactions. This is less of a concern for candesartan, which is not extensively metabolized by the liver.

3.     Hyperkalaemia: As with other ARBs, there's a risk of hyperkalemia, which could be particularly problematic in patients with renal impairment or those on concurrent medications that increase serum potassium levels.

4.     Hypotension: Although beneficial for hypertension, the blood pressure-lowering effects could pose a risk of hypotension, especially in dehydrated or volume-depleted patients, which can be a concern in post-COVID conditions.  In practical use, low dose candesartan is best suited given is reduced potency and shorter half-life.

 

Summary:

 

Angiotensin II AT1 Receptor Blockers, (ARBs) are neuroprotective, significantly reducing glutamate-induced neuronal injury and apoptosis.   Telmisartan was the most potent ARB studied, with an order of potency telmisartan > candesartan > losartan > valsartan.(20)

Consequently, decreasing AT1R activity with the AT1R antagonists, angiotensin II receptor blockers (ARBs) is therapeutically efficacious in rodent models of cerebral haemorrhage, Parkinson’s disease, Alzheimer’s disease and brain inflammation (21)

PPARγ activation was also involved in the neuroprotective effects of telmisartan, as telmisartan enhanced PPARγ nuclear translocation. These results substantiate the therapeutic use of ARBs, in particular telmisartan, in neurodegenerative diseases and traumatic brain disorders where glutamate neurotoxicity plays a significant role. (20)

 

Choice of medication may be governed by co-morbidities, peripheral blood pressure, renal or hepatic function.   It must be noted that the use of the sartans in Long COVID has not been authorized by the TGA.


References:


1.     Lukito AA, Widysanto A, Lemuel TAY, Prasetya IB, Massie B, Yuniarti M, Lumbuun N, Pranata R, Meidy C, Wahjoepramono EJ, Yusuf I. Candesartan as a tentative treatment for COVID-19: A prospective non-randomized open-label study. Int J Infect Dis. 2021 Jul;108:159-166. doi: 10.1016/j.ijid.2021.05.019. Epub 2021 May 24. PMID: 34038766; PMCID: PMC8142270.

2.     Fujita T, Hirooka K, Nakamura T, Itano T, Nishiyama A, Nagai Y, Shiraga F. Neuroprotective effects of angiotensin II type 1 receptor (AT1-R) blocker via modulating AT1-R signaling and decreased extracellular glutamate levels. Invest Ophthalmol Vis Sci. 2012 Jun 26;53(7):4099-110. doi: 10.1167/iovs.11-9167. PMID: 22661470.

3.     Weatherston, A. Candesartan potential therapeutic for Alzheimer’s disease. Neuro Central. 2016. https://www.neuro-central.com/potential-role-of-candesartan-in-alzheimers-treatment/

4.     Zheng, M., Karki, R., Williams, E.P. et al. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nat Immunol 22, 829–838 (2021). https://doi.org/10.1038/s41590-021-00937-x

5.     Torika N, Asraf K, Apte RN, Fleisher-Berkovich S. Candesartan ameliorates brain inflammation associated with Alzheimer's disease. CNS Neurosci Ther. 2018 Mar;24(3):231-242. doi: 10.1111/cns.12802. Epub 2018 Jan 24. PMID: 29365370; PMCID: PMC6489976.

6.     Torika N, Asraf K, Danon A, Apte RN, Fleisher-Berkovich S. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies. PLoS One. 2016 May 17;11(5):e0155823. doi: 10.1371/journal.pone.0155823. PMID: 27187688; PMCID: PMC4871324.

7.     Villapol S, Balarezo MG, Affram K, Saavedra JM, Symes AJ. Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Brain. 2015 Nov;138(Pt 11):3299-315. doi: 10.1093/brain/awv172. Epub 2015 Jun 26. PMID: 26115674; PMCID: PMC4731413.

8.     Pelliccia F, Pasceri V, Cianfrocca C, Vitale C, Speciale G, Gaudio C, Rosano GM, Mercuro G. Angiotensin II receptor antagonism with telmisartan increases number of endothelial progenitor cells in normotensive patients with coronary artery disease: a randomized, double-blind, placebo-controlled study. Atherosclerosis. 2010 Jun;210(2):510-5. doi: 10.1016/j.atherosclerosis.2009.12.005. Epub 2009 Dec 11. PMID: 20044087.

9.     Stierschneider A, Wiesner C. Shedding light on the molecular and regulatory mechanisms of TLR4 signaling in endothelial cells under physiological and inflamed conditions. Front Immunol. 2023 Nov 24;14:1264889. doi: 10.3389/fimmu.2023.1264889. PMID: 38077393; PMCID: PMC10704247.

10.  Saavedra JM, Benicky J, Zhou J . Mechanisms of the anti-ischemic effect of angiotensin II AT(1) receptor antagonists in the brain. Cell Mol Neurobiol 2006; 26: 1099–1111.

11.  Sprenger T, Viana M, Tassorelli C. Current Prophylactic Medications for Migraine and Their Potential Mechanisms of Action. Neurotherapeutics. 2018 Apr;15(2):313-323. doi: 10.1007/s13311-018-0621-8. PMID: 29671241; PMCID: PMC5935650.

12.  Yi W, Chen F, Zhang H, Tang P, Yuan M, Wen J, Wang S, Cai Z. Role of angiotensin II in aging. Front Aging Neurosci. 2022 Dec 2;14:1002138. doi: 10.3389/fnagi.2022.1002138. PMID: 36533172; PMCID: PMC9755866.

13.  Zhang X, Dong Y, Dong H, Cui Y, Du Q, Wang X, Li L, Zhang H. Telmisartan Mitigates TNF-α-Induced Type II Collagen Reduction by Upregulating SOX-9. ACS Omega. 2021 Apr 22;6(17):11756-11761. doi: 10.1021/acsomega.1c01170. PMID: 34056329; PMCID: PMC8154015.

14.  Kurokawa H, Sugiyama S, Nozaki T, Sugamura K, Toyama K, Matsubara J, Fujisue K, Ohba K, Maeda H, Konishi M, Akiyama E, Sumida H, Izumiya Y, Yasuda O, Kim-Mitsuyama S, Ogawa H. Telmisartan enhances mitochondrial activity and alters cellular functions in human coronary artery endothelial cells via AMP-activated protein kinase pathway. Atherosclerosis. 2015 Apr;239(2):375-85. doi: 10.1016/j.atherosclerosis.2015.01.037. Epub 2015 Jan 31. PMID: 25682036.

15.  Honda A, Matsuura K, Fukushima N, Tsurumi Y, Kasanuki H, Hagiwara N. Telmisartan induces proliferation of human endothelial progenitor cells via PPARgamma-dependent PI3K/Akt pathway. Atherosclerosis. 2009 Aug;205(2):376-84. doi: 10.1016/j.atherosclerosis.2008.12.036. Epub 2008 Dec 31. PMID: 19193378.

16.  Sariol, A., Perlman, S. SARS-CoV-2 takes its Toll. Nat Immunol 22, 801–802 (2021). https://doi.org/10.1038/s41590-021-00962-w

17.  Benson,S et al. Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist With Selective PPARγ–Modulating Activity. Hypertension, 2004. https://doi.org/10.1161/01.HYP.0000123072.34629.57

18.  Uehara G, Takeda H. Relative effects of telmisartan, candesartan and losartan on alleviating arterial stiffness in patients with hypertension complicated by diabetes mellitus: an evaluation using the cardio-ankle vascular index (CAVI). J Int Med Res. 2008 Sep-Oct;36(5):1094-102. doi: 10.1177/147323000803600529. PMID: 18831906.

19.  Zhang P, Hou Y, Tu W, Campbell N, Pieper AA, Leverenz JB, Gao S, Cummings J, Cheng F. Population-based discovery and Mendelian randomization analysis identify telmisartan as a candidate medicine for Alzheimer's disease in African Americans. Alzheimers Dement. 2023 May;19(5):1876-1887. doi: 10.1002/alz.12819. Epub 2022 Nov 4. PMID: 36331056; PMCID: PMC10156891.

20.  Wang J, Pang T, Hafko R, Benicky J, Sanchez-Lemus E, Saavedra JM. Telmisartan ameliorates glutamate-induced neurotoxicity: roles of AT(1) receptor blockade and PPARγ activation. Neuropharmacology. 2014 Apr;79:249-61. doi: 10.1016/j.neuropharm.2013.11.022. Epub 2013 Dec 4. PMID: 24316465; PMCID: PMC3950310.

21.  Stierschneider A, Wiesner C. Shedding light on the molecular and regulatory mechanisms of TLR4 signaling in endothelial cells under physiological and inflamed conditions. Front Immunol. 2023 Nov 24;14:1264889. doi: 10.3389/fimmu.2023.1264889. PMID: 38077393; PMCID: PMC10704247.

 

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