Telmisartan and Candesartan in Mitigating Cognitive Impairment in Long COVID

Dr Graham Exelby May 2024, revised May 2025

Abstract

Angiotensin II receptor blockers (ARBs), particularly telmisartan and candesartan, show promise in treating cognitive impairment in Long COVID by reducing brain inflammation, protecting blood vessels, and enhancing neuroplasticity.

We hypothesize that these ARBs can improve memory and executive function by targeting neuroinflammation and vascular dysfunction. Telmisartan’s superior brain penetration and PPAR-γ activation may offer broader benefits, while candesartan excels in long-term cognitive recovery. Their established safety in cardiovascular populations and preclinical evidence support their repurposing for Long COVID, with clinical trials urgently needed to validate efficacy.

Introduction

Cognitive impairment in Long COVID, characterized by memory loss, reduced executive function, and mental fatigue, poses a significant clinical challenge. Neuroimaging and molecular studies point to brain endothelial dysfunction, chronic neuroinflammation, glymphatic stagnation, and excitotoxic injury as key drivers. While no standard treatment exists, repurposing medications with targeted actions is a promising strategy.

Angiotensin II type 1 receptor blockers (ARBs), such as telmisartan and candesartan, offer multifaceted benefits beyond blood pressure control, including anti-inflammatory effects, blood-brain barrier (BBB) penetration, and modulation of microglial reactivity. Telmisartan’s longer half-life, lipophilicity, and PPAR-γ activation provide distinct neuroprotective advantages over candesartan. This paper reviews the pathophysiology of Long COVID cognitive impairment, compares the therapeutic potential of candesartan and telmisartan, and proposes future research directions to address this debilitating condition.

Pathophysiological Insights into Long COVID Cognitive Impairment

Long COVID-related cognitive dysfunction—often termed “brain fog”—is increasingly understood as a neurovascular–immune–metabolic disorder. Emerging evidence supports the convergence of the following pathological mechanisms:

• Chronic Neuroinflammation and Glial Sensitization: SARS-CoV-2 triggers sustained activation of microglia and astrocytes via pattern recognition receptors (TLR4, RAGE), leading to NF-κB–mediated production of IL-1β, TNF-α, and CCL2. This feedback loop induces a state of central sensitization and impairs synaptic plasticity.

• Cerebrovascular Dysfunction: Endothelial injury, microthrombi, and BBB disruption are common, driven by angiotensin II–induced vasoconstriction and oxidative stress. These alterations precipitate hypoperfusion, especially in the brainstem, basal ganglia, and frontal cortex—regions implicated in executive dysfunction.

• Glymphatic Stagnation: Disruption of perivascular clearance due to impaired aquaporin-4 (AQP4) function and venous congestion exacerbates neuroinflammatory burden. Standing-induced spreading hypoperfusion (as seen in SPECT studies) further impairs glymphatic efficiency.

• Glutamate Excitotoxicity and GABA Dysregulation: Persistent neuroinflammation skews the GABA–glutamate balance, often observed in Long COVID patients with low GABA and aspartate, and elevated glutamate. This neurochemical profile contributes to cortical hyperexcitability and fatigue.

• Mitochondrial Dysfunction and NAD⁺ Depletion: Viral persistence, oxidative stress, and PDH inhibition drive metabolic inflexibility. Nicotinamide riboside deficiency and impaired SIRT1/3 activation reduce neuronal resilience and repair capacity.

These mechanisms jointly underpin the cognitive deficits of Long COVID and suggest therapeutic targets: immune modulation (RAGE/TLR4/NF-κB), vascular stabilization, glutamate control, glymphatic flow restoration, and mitochondrial repair.

Additional Evidence from Alzheimer’s Disease Model

Further supporting telmisartan’s neuroprotective profile, a 2022 study by Torika et al.(21) using a mouse model of familial Alzheimer’s disease demonstrated that intranasal administration of telmisartan markedly reduced amyloid-β plaque burden, glial activation, and proinflammatory cytokine levels, while preserving neuronal integrity and improving spatial memory performance The intranasal route facilitated direct CNS access, bypassing the blood–brain barrier, and likely enhanced drug delivery to the glymphatic interface and autonomic brainstem nuclei.

Mechanistically, this effect was attributed to dual AT1R blockade (reducing NADPH oxidase–mediated ROS generation and downstream NF-κB signalling) and PPAR-γ activation, which enhanced mitochondrial resilience and microglial phenotypic switching. The pronounced suppression of TNF-α, IL-6, Iba-1, and GFAP, along with improvements in Morris water maze performance, aligns with telmisartan’s relevance in addressing neuroinflammation and cognitive impairment in Long COVID.

These findings substantiate telmisartan’s translational potential for neuroinflammatory syndromes beyond Alzheimer’s disease, particularly in contexts involving glymphatic congestion, central sensitization, and impaired waste clearance—core features of Long COVID cognitive decline. Notably, the authors proposed that intranasal delivery may enhance access to brainstem and perivascular lymphatic zones, offering mechanistic synergy with your ongoing glymphatic and lymphatic hypotheses in POTS and Long COVID.  At this stage, we are using oral telmisartan and await research support for the intranasal delivery.

Mechanistic Insights on neuronal stabilization

Villapol et al. 2015 (6) demonstrated that both telmisartan and candesartan reduce neuronal apoptosis, glial reactivity, and lesion burden following traumatic brain injury (TBI), confirming their dual mechanism via AT1R blockade and PPARγ activation. Their study highlights the necessity of early intervention (within 6 hours post-injury), with both drugs failing to show benefit if delayed to 24 hours. Telmisartan excelled in early motor recovery, while candesartan offered more robust long-term cognitive benefits, underscoring potential for endotype-guided therapy.

Notably, direct anti-inflammatory effects on cultured glia (telmisartan blocked LPS-induced iNOS and IL-1β in microglia) were PPARγ-dependent. These findings strongly support the use of telmisartan in neuroinflammatory states with glial overactivation, such as Long COVID and POTS.

Glutamate Excitotoxicity and NR2B–PPARγ Signalling

Wang et al .2014 (19) described telmisartan’s protective role against glutamate-induced neurotoxicity via NR2B receptor modulation. This mechanism operates independently of AT1R, involving suppression of NR2B-associated signalling, inhibition of the JNK/c-Jun apoptotic axis, and preservation of mitochondrial integrity. Given the elevated glutamate and depleted GABA/aspartate profiles in many Long COVID and POTS patients, this PPARγ-dependent modulation of excitotoxic pathways represents a critical therapeutic target.

These findings provide molecular justification for telmisartan’s use in patients with redox imbalance, amino acid dysregulation, and central sensitization. They also extend its indications beyond vascular tone control toward glutamate–GABA system stabilization.

Telmisartan’s Expanded Role: Astrocyte–IL-6–STAT3 Axis Modulation

A 2024 study by Quan et al. significantly advances our understanding of telmisartan’s neuroimmune properties. Using a glioma–astrocyte co-culture model, low-dose telmisartan (5 μM) was shown to suppress astrocytic IL-6 production via PPAR-γ–dependent inhibition of NF-κB (p65) phosphorylation. This led to reduced STAT3 activation in adjacent glioma cells, which in turn downregulated pro-proliferative and migratory mediators such as Cyclin B1, MMP2, and MMP9.

These findings are relevant to Long COVID, where a persistent IL-6–STAT3 loop contributes to glial activation, cortical sensitization, and fatigue. Notably, telmisartan’s effects were independent of angiotensin II type 1 receptor blockade and were abrogated by a PPAR-γ antagonist. This supports a unique immunometabolic profile of telmisartan, targeting astrocyte-driven paracrine amplification in chronic neuroinflammation.

Such a mechanism may underlie telmisartan’s observed ability to reduce central fatigue and brainstem hypoperfusion, especially in patients with chronic IL-6 elevation and glymphatic dysfunction. Its glial-selective action supports use in neuroinflammatory states like Long COVID, ME/CFS, and POTS.

Therapeutic Potential of Candesartan and Telmisartan

Candesartan:

• Neuroprotective Effects: Reduces neuroinflammation and amyloid-beta accumulation in preclinical models.

• Cognitive Benefits: Improves cognitive performance in animal studies via modulation of the renin-angiotensin system (RAS) and attenuation of oxidative stress.

Telmisartan:

• PPAR-γ Activation: Acts as a partial agonist of PPAR-γ, promoting anti-inflammatory and insulin-sensitizing effects.

• Cognitive Enhancement: Upregulates brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the hippocampus, improving learning and memory in hypertensive rat models.

Hypothesis:

We hypothesize that candesartan and telmisartan can improve cognitive impairment in Long COVID by addressing neuroinflammation, vascular dysfunction, and neuronal injury.

A 2020 study found that candesartan reduced hospital stay length in non-obese COVID-19 patients, though it did not address Long COVID or cognitive outcomes (1). No further evidence supports its continued use in this context. Given their established mechanisms, we propose candesartan and telmisartan as candidates for Long COVID cognitive impairment treatment, despite lacking TGA approval.

Co-morbidities and Mechanisms:

Co-morbidities like migraine, Alzheimer’s disease, stroke, and traumatic brain injury are critical in Long COVID management. Both ARBs:

• Block angiotensin II type 1 receptor (AT1R), reducing excitotoxicity and oxidative damage via glutamate regulation (2).

• Cross the BBB, enabling direct CNS effects to mitigate neuroinflammation (3).

• Modulate microglial and astrocyte dysfunction, reducing inflammatory mediators like TNF-α and IL-1β (4, 5).

• Protect against Alzheimer’s pathology by decreasing amyloid-beta and modulating glial activation (4, 5).

• Potentially influence telomerase activity, reducing telomere shortening and cellular aging (12).

  
  

Traumatic Brain Injury and Comparative Efficacy

In traumatic brain injury (TBI) models, both ARBs reduce lesion volume, neuronal injury, and inflammation at non-hypotensive doses (0.1 mg/kg candesartan, 1 mg/kg telmisartan) (7). They protect cerebral blood flow and enhance recovery through AT1R blockade and PPAR-γ activation. Candesartan shows superior long-term cognitive benefits, while telmisartan excels in acute motor recovery (7). These effects are relevant to Long COVID’s neurovascular pathology.

Stroke

Telmisartan improves cerebral circulation in hypertensive patients with chronic stroke, maintaining blood flow despite blood pressure reduction, likely via PPAR-γ agonism and endothelial nitric oxide synthase (eNOS) upregulation (7, 10). Candesartan shares similar autoregulatory benefits.

Migraine

Candesartan is effective in migraine prophylaxis, likely by modulating CNS excitability, preserving BBB integrity, and reducing glutamate-induced excitotoxicity (11). Telmisartan’s potential in migraine is less studied but theoretically supported by its vascular and anti-inflammatory effects.

Intracranial Hypertension and Vascular Dynamics

Long COVID patients often exhibit brainstem hypoperfusion and hyperperfused brain SPECT findings, reflecting endotheliitis and BBB dysfunction. The glymphatic system, critical for cerebral waste clearance, is impaired in these conditions. ARBs may enhance glymphatic flow by reducing neuroinflammation and optimizing RAS-mediated fluid dynamics (7).

Telomerase Connection

Both ARBs may enhance telomerase activity, reducing telomere shortening in endothelial cells and potentially protecting against vascular and neuronal aging (12). Telmisartan’s PPAR-γ activation further supports these effects, offering cardiovascular and neuroprotective benefits.

Comparative Analysis

Candesartan and telmisartan share similarities but differ in key aspects, as summarized below:

Feature	Candesartan	Telmisartan
Half-Life	9-12 hours	24 hours
PPAR-γ Activation	Minimal (in vivo only)	Strong (partial agonist)
BBB Penetration	Good	Superior (high lipophilicity)
Cognitive Benefits	Stronger long-term	Stronger short-term
Motor Recovery	Limited	Better in acute phase
Unique Effects	TLR2 inhibition, amyloid-beta reduction	Metabolic regulation, BDNF upregulation

Similarities: Both reduce lesion volume, neuronal injury, and inflammation in TBI models at non-hypotensive doses. They improve glymphatic flow and cerebral homeostasis via RAS modulation.

Differences: Telmisartan’s PPAR-γ activation and better BBB penetration enhance acute neuroprotection and metabolic regulation. Candesartan’s potent AT1R blockade and TLR2 inhibition favor long-term cognitive outcomes. No clinical trials directly compare them for Long COVID cognitive impairment.

Synergistic Potential of Telmisartan and Nicotinamide Riboside

Combining telmisartan with nicotinamide riboside (NR), a NAD⁺ precursor, targets multiple Long COVID pathways:

• Mitochondrial Function: NR boosts NAD⁺ levels, activating SIRT1/SIRT3, while telmisartan enhances fatty acid oxidation via PPAR-γ.

• Neuroinflammation: NR suppresses NF-κB, and telmisartan shifts microglia to an anti-inflammatory state.

• Vascular Protection: Both upregulate eNOS, improving BBB integrity and glymphatic clearance.

• Metabolic Regulation: NR activates AMPK, and telmisartan promotes insulin sensitivity.

This synergy supports clinical trials to explore dual-agent therapy for Long COVID cognitive impairment.

Evolving Pathophysiology in Long COVID: Telmisartan's Dual Role in Cytokine and Hypoxia Modulation

As Long COVID progresses, there appears to be a clinical transition from cytokine-dominant pathology to a hypoxia-dominant neurovascular impairment, particularly in patients with ongoing endothelial dysfunction, mast cell activation, and microvascular congestion. Telmisartan’s unique dual mechanism—as both an angiotensin II type 1 receptor (AT1R) blocker and partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist—offers multifaceted benefits across this continuum.

1. Anti-Cytokine Action via PPAR-γ Agonism

PPAR-γ is a nuclear receptor that downregulates pro-inflammatory transcription pathways, including NF-κB. Telmisartan's selective PPAR-γ activity—confirmed in vitro by Benson et al. 2005 (16) attenuates TNF-α, IL-6, and CCL2, all of which are elevated in Long COVID and contribute to persistent glial activation, hippocampal dysfunction, and cortical sensitization.

This aligns with the findings of Ciavarella et al. 2021 (22), who proposed PPAR-γ agonists for cytokine storm mitigation, making telmisartan highly relevant in early- to mid-stage inflammatory Long COVID.

2. RAS Modulation and Vascular Repair

Telmisartan blocks the pathological arm of the renin-angiotensin system (angiotensin II → AT1R), which is amplified in SARS-CoV-2 due to ACE2 depletion. This blockade reduces vasoconstriction, microvascular oxidative stress, and sympathetic overactivation. Importantly, it also preserves endothelial function and may restore glymphatic and hippocampal perfusion.(Rothlin et al 2020 (23)

3. Synergy with Other Immune Modulators

Clinically, telmisartan could be co-administered with H1/H2 antihistamines and low-dose naltrexone (LDN). Antihistamines suppress mast cell–derived cytokines and reduce histamine-induced neurovascular permeability. LDN reduces glial priming via TLR4 antagonism and endorphin upregulation.

Telmisartan complements both: PPAR-γ agonism may inhibit mast cell–derived prostaglandin D2, while AT1R blockade mitigates hypoxia-induced RAGE ligand release.

4. Metabolic Regulation and Brain Energy Recovery

In chronic Long COVID, neuroenergetic deficits emerge due to PDH inhibition, NAD⁺ depletion, and impaired fatty acid oxidation. Telmisartan—via PPAR-γ activation—enhances mitochondrial biogenesis, boosts eNOS, and improves insulin sensitivity, synergizing well with nicotinamide riboside and magnesium to restore redox homeostasis and ATP availability.

Summary

Long COVID-related cognitive impairment is now recognized as a multifactorial syndrome driven by neuroinflammation, cerebral hypoperfusion, glymphatic stagnation, and mitochondrial dysfunction. Central to this is the chronic activation of glial cells via immune pathways such as TLR4 and RAGE, which drive excitotoxicity, BBB breakdown, and impaired synaptic function. Disruption in amino acid metabolism—including low GABA, aspartate, and ethanolamine with elevated glutamate—further contributes to neurocognitive decline and central sensitization.

Angiotensin II receptor blockers (ARBs), particularly candesartan and telmisartan, offer mechanistically aligned therapeutic potential. Both agents improve cerebral perfusion and reduce inflammation at non-hypotensive doses by blocking AT1R signalling.

Telmisartan’s strong blood-brain barrier penetration and partial PPAR-γ agonism uniquely enable it to modulate mitochondrial function, suppress NF-κB and CCL2 activity, and enhance neurotrophic support via BDNF.

Candesartan, while less metabolically active, provides robust long-term neuroprotection, including amyloid-beta modulation and TLR2 inhibition, relevant to patients with overlapping neurodegenerative risk.

The combination of telmisartan with nicotinamide riboside may amplify benefits by restoring NAD⁺ levels, enhancing SIRT activity, and reversing neuroenergetic deficits. Given their safety and pleiotropic actions, these ARBs are promising candidates for clinical trials in Long COVID cognitive impairment, with telmisartan emerging as a particularly well-suited first-line agent.

Conclusion

Telmisartan and candesartan offer compelling therapeutic potential for mitigating cognitive impairment in Long COVID through pleiotropic neurovascular and immune-modulating mechanisms. While both ARBs exert anti-inflammatory and endothelial-protective effects, telmisartan’s unique PPAR-γ agonist activity confers additional benefits by directly suppressing astrocyte-derived IL-6 and downstream STAT3 signalling—critical mediators of glial-driven neuroinflammation and cortical sensitization.

Recent evidence from glioma–astrocyte co-culture models (Quan et al., 2024) demonstrates that low-dose telmisartan exerts a glial-selective, paracrine-modulating effect that is independent of AT1R blockade. This supports its utility in neuroimmune conditions such as Long COVID, ME/CFS, and POTS, where persistent IL-6/STAT3 loops, mitochondrial dysfunction, and glymphatic congestion are key pathological features.

Given its strong BBB permeability, metabolic advantages, and mechanistic relevance across multiple Long COVID endotypes, telmisartan emerges as a promising first-line ARB candidate—particularly when combined with agents like nicotinamide riboside for mitochondrial restoration. Urgent biomarker-guided trials are warranted to evaluate its efficacy in reversing neuroinflammatory signatures and improving cognitive outcomes in affected patients. 

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