2.6. Neuroprotective effects of benfotiamine

Neuroprotective effects of benfotiamine were first observed when it was used in the treatment of neuropathies associated with diabetes [[65], [66], [67]]. Patients that received benfotiamine had a significant improvement in the neuropathy score when compared to placebo [67]. Furthermore, benfotiamine was shown to be effective in treating patients with alcoholic polyneuropathy [68]. This was further investigated in 2013, when Manzardo et al. conducted a double-blind, randomized placebo-controlled clinical trial investigating benfotiamine efficacy in treating alcohol dependence. Participants received 600 mg of benfotiamine or placebo, once a day for 24 weeks. Even though alcohol consumption decreased for both groups, the reduction was significantly greater in benfotiamine treated women, leading the authors to conclude that benfotiamine could be examined as an effective adjuvant therapy in treating alcoholism [62]. However, no follow-up clinical trial was conducted afterwards.

Several neurodegenerative diseases have been associated with diminished activity of thiamine-dependent enzymes, including Alzheimerˈs disease (AD), Parkinsonˈs disease, Huntington's disease, Wernicke–Korsakoff syndrome, and others [69]. In AD patients, the reductions in thiamine-dependent processes have been correlated with clinical symptoms of dementia [70]. However, treatment with thiamine hydrochloride did not lead to improvement in symptoms of AD [71]. The first study that linked benfotiamine to treatment of AD was published in 2010 [20]. The authors showed that chronic (8 week) treatment of benfotiamine improved spatial memory, and reduced amyloid plaque and phosphorylated tau levels in amyloid precursor protein (APP)/presenilin-1 transgenic mice. These effects were specifically attributed to benfotiamine, considering that neither fursultiamine nor high doses of thiamine produced a similar result. The authors found that benfotiamine enhanced phosphorylation of glycogen synthase kinase (GSK), which leads to the suppression of its activity, and they proposed that this is the mechanism through which benfotiamine exerts its protective effects in the AD model, seeing that GSK has been involved in tau phosphorylation [72] and the production and accumulation of β-amyloid in APP overexpressing mice [20]. Subsequently, other studies also found that benfotiamine inhibits GSK [22,73,74]. This mechanism was further examined in in vitro model, where it was shown that benfotiamine suppresses β-amyloid production in HEK cells, while also enhancing the ratio of phosphorylated GSK/GSK, thus inhibiting its activity [73]. In streptozotocin-induced model of AD benfotiamine reduced cognitive deficit, following the increase in ThDP concentrations in hippocampus and entorhinal cortex, brain regions important for memory. These effects were contributed to increase in energy metabolism, insulin signaling pathway and suppression of GSK3α/β and ERK 1/2 activity. Additionally, benfotiamine increased the expression of glutamate subunit 2B (GluN2B) of NMDA-type receptors in the hippocampus and entorhinal cortex, important for long-term potentiation and memory formation [22]. In a transgenic mouse model of tauopathy, benfotiamine also showed neuroprotective effects, increasing lifespan, improving behavioral deficits, decreasing generation of neurofibrillary tangles and preventing death of motor neurons. Furthermore, benfotiamine decreased inflammation, oxidative stress and mitochondrial dysfunction. When investigating the underlying mechanism, the authors did not find changes in GSK phosphorylation, but showed that benfotiamine exerts its effects by activating Nrf2, master regulator of oxidative stress response, to translocate to the nucleus and activate transcription of antioxidative genes [21]. Besides the effect on cognitive function, benfotiamine suppressed changes in hypothalamic insulin signaling in a rat model of AD, which resulted in improvement of the metabolic profile [23].

These promising results in animal studies led to clinical trials of benfotiamine treatment to investigate whether it could be beneficial for patients with AD. In 2016, Pan et al. conducted a small, uncontrolled clinical study on five patients with mild to moderate AD. They found that daily supplementation with 300 mg of benfotiamine during 18 months had improved the cognitive abilities of patients, independently of brain amyloid accumulation [24]. In 2020, Gibson et al. performed double-blind early phase II randomized placebo controlled clinical trial to assess whether benfotiamine is safe, efficacious and feasible for patients with mild cognitive impairment or mild dementia. Patients were treated with 300 mg of benfotiamine or placebo, twice a day for 12 months. Benfotiamine treatment was safe and effective in raising thiamine concentrations in the periphery. Importantly, benfotiamine was effective in suppressing cognitive decline, as measured by Alzheimerˈs disease assessment scale and clinical dementia rating. It also reduced increases in advanced glycation end products [25]. These encouraging results warrant a larger clinical trial to confirm these findings.

Other than treatment for AD, benfotiamine has been shown to be effective in reducing stress induced behavioral and molecular pathologies in animal models [[74], [75], [76]]. Specifically, Markova et al. showed that benfotiamine improved cognition in a mouse model of predator stress and forced swimming and these changes were connected to its effect on GSK-3β activity [74]. Another study showed that benfotiamine prevents stress-impaired adult hippocampal neurogenesis, as well as stress-induced bodyweight loss, anxiety-like behavior and oxidative stress in mice [75]. Additionally, it was shown that benfotiamine prevented ultrasound-induced aggression in a mouse model, while also ameliorating changes in glutamate subunit A1 and A2 and decreasing oxidative stress [76]. Results of these animal studies suggest that benfotiamine could be explored as a neuroprotective agent in various neurological and psychiatric diseases.