Multi-target drugs for the treatment of cognitive impairment and fatigue in post-COVID syndrome: focus on Ginkgo biloba and Rhodiola rosea

Abstract

Cognitive impairment, depression and (mental) fatigue represent the most frequent neuropsychiatric symptoms of the post-COVID syndrome. Neuroinflammation, oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological mechanisms underlying these symptoms. Attempts to treat post-COVID-associated cognitive impairment and fatigue with different drugs available for other diseases have not yet been successful. One probable explanation could be that these drugs work by one specific mechanism of action only and not in a broad multi-target way. Therefore, they will not address the broad pathophysiological spectrum possibly responsible for cognitive impairment, depression and fatigue in post-COVID syndrome. Notably, nearly all drugs currently under investigation for fatigue in post-COVID syndrome are rather addressing one single target instead of the several pathomechanisms underlying this condition. Contrary to this approach, herbal drugs often consist of many different ingredients with different pharmacological properties and pharmacological targets. Therefore, these drugs might be a promising approach for the treatment of the broad symptomatic presentation and the pathophysiological mechanisms of cognitive impairment and fatigue following a SARS-CoV-2 infection. Of these herbal drugs, extracts of Ginkgo biloba and Rhodiola rosea probably are the best investigated candidates. Their broad pharmacological spectrum in vitro and in vivo includes anti-oxidative, anti-inflammatory, antidepressant as well as properties reducing cognitive impairment and fatigue. In several studies, both drugs showed positive effects on physical and mental fatigue and impaired cognition. Moreover, depressive symptoms were also reduced in some studies. However, even if these results are promising, the data are still preliminary and require additional proof by further studies.

Management of cognitive impairment associated with post-COVID-19 syndrome: recommendations for primary care

“…Most published nonclinical and clinical studies investigating Ginkgo biloba extract were done using the proprietary Ginkgo biloba leaves extract EGb 761 ® . EGb 761 ® was shown to display multimodal effects on a variety of pathogenetic processes which may be involved in PCS ( Mueller and Muller, 2024 ). Flavonoids, terpenoids, and anthocyanidins exhibit neuroprotective effects by modulating signaling pathways known to be impacted by COVID-19 ( Zaa et al, 2023 ).…”

“…A meta-analysis of seven randomized, placebo-controlled trials in patients with dementia showed that treatment-associated risks (relative risk of adverse events, rates of premature withdrawal) in patients taking EGb 761 ® did not differ noticeably compared to the placebo group and confirmed the safety and tolerability of this extract ( Gauthier and Schlaefke, 2014 ). However, even if these pharmacological and clinical results are promising, the available data are still preliminary and require additional proof by further studies ( Mueller and Muller, 2024 ).…”

Ginkgo biloba: A Leaf of Hope in the Fight Against Alzheimer’s Dementia: Clinical Trial Systematic Review

“…Similarly, GB extract (GBE) has a broad pharmacological spectrum for preventing oxidative stress, which protects the central nervous system from depressive processes, improves aspects of impaired neuroplasticity, and increases cellular mitochondrial function (Figure 2). Secondarily, GBE's antioxidant and anti-inflammatory properties improve the prognosis of cardiovascular diseases [158][159][160][161].…”

Ginkgo biloba: A Leaf of Hope in the Fight against Alzheimer’s Dementia: Clinical Trial Systematic Review

“…Similarly, GB extract (GBE) has a broad pharmacological spectrum for preventing oxidative stress, which protects the central nervous system from depressive processes, improves aspects of impaired neuroplasticity, and increases cellular mitochondrial function ( Figure 2 and Figure 6 ). Secondarily, GBE’s antioxidant and anti-inflammatory properties improve the prognosis of cardiovascular diseases [ 161 , 162 , 163 , 164 ].…”