Anti-inflammatory Effects of Homotaurine in Patients With Amnestic Mild Cognitive Impairment

Abstract

Alzheimer’s disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the in vivo homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers (n = 9) or no carriers (n = 11) of the ε4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1β, Tumor necrosis factor-alpha (TNFα), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFβ), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEε4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression.

Neurobiological Highlights of Cognitive Impairment in Psychiatric Disorders

“…Homotaurine is a potential therapeutic compound for AD, as it has anti-inflammatory properties. After taking homotaurine, patients carrying the APOEε4 allele demonstrated a significant decrease in the level of IL-18 (but not other cytokines) [239].…”

A Review on Tramiprosate (Homotaurine) in Alzheimer's Disease and Other Neurocognitive Disorders

“…Mechanisms of action of tramiprosate include effects on amyloid, but also anti-inflammatory effects as demonstrated in MCI patients ( 32 , 33 ). A third mechanism of action is linked to the GABA-A receptor (GABA-AR).…”

“…In this line, a recent study evaluating tramiprosate administration in aMCI patients also showed improved short-term episodic memory performance in ApoE4/4 carriers. In addition to neuropsychological and functional assessments, cytokine levels were performed at baseline and after 1 year, and a significant decrease in IL-18 serum levels was observed, suggesting a drug-related anti-inflammatory effect ( 32 ). Another study in patients with symptomatic MCI showed an even earlier response.…”

Perspectives on the Role of APOE4 as a Therapeutic Target for Alzheimer’s Disease

“…Recently APOE ɛ 4 has emerged as a promising therapeutic target for treatment of AD as it plays key role in triggering the disease [ 107 ]. Studies suggest that AD progression can be avoided by targeting APOE ɛ 4 gene and gene products as well as its functions with the aid of the above mentioned approaches [ 108 ]. Immunomodulation with ApoE4 monoclonal antibodies, mimesis through peptides of ApoE and ApoE4 degradation may be helpful as a promising approach for delaying the onset of disease.…”