B1 for Parkinson's Blog

Q&A on benfotiamine

What is benfotiamine?

Benfotiamine is a thioester synthetic thiamine derivative, a thiamine precursor.

What is thiamine and which role does it have in the cell?

Thiamine is vitamin B1. After entering the cells, thiamine is converted into its active form, thiamine diphosphate (ThDP), also known as TPP (thiamine pyrophosphate). ThDP acts as a cofactor (“helper”) in key enzymatic processes which play a key role in glucose and energy metabolism, biosynthesis and antioxidant activity, such as those involving transketolase and the mitochondrial pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes, which are also needed to produce key neurotransmitters (acetylcholine, glutamate, GABA) (Bettendorff, 2023; Mkrtchyan, 2015).

Impaired glucose metabolism plays a role in the pathophysiology of Parkinson’s, together with other factors (e.g. oxidative stress and neuroinflammation). Glucose metabolism is key to cellular energy production and neurons rely on glucose as the primary source of energy. Decreased activity of ThDP–dependent enzymes adversely affects glucose metabolism in the brain. In Parkinson’s, glucose metabolism is impaired in neurons even at the early stages of the disease (Dunn, 2014).

Is there any thiamine deficiency in diabetes and neurodegenerative diseases?

Diabetes - Thiamine deficiency is often present in type 2 diabetes mellitus (Rabbani, 2011; Muley, 2022). Since the active form of thiamine, ThDP, is a cofactor also of transketolase, thiamine deficiency is accompanied by a reduced activity of transketolase and transketolase-dependent processes (Coy, 2005; Ge, 2020), which may play a role in inducing diabetic vascular complications (Ge, 2020).

Alzheimer’s disease - Glucose metabolism and thiamine-dependent processes are reduced in the brain of persons with Alzheimer’s disease at autopsy and are an indicator of disease progression (Butterworth, 1990; Pan, 2010; Gibson, 1988, 2000, 2013; Mkrtchyan, 2015; Tapias, 2018; Moraes, 2020). Plasma thiamine levels have been found to be lower in persons with Alzheimer’s than in persons with Parkinson’s disease (Gold, 1998).

Why has benfotiamine been developed?

When given orally, thiamine absorption is low. The oral route is largely influenced by a low and unpredictable rate of absorption in persons with Parkinson’s disease, most of whom suffer from gastrointestinal disorders (Csoti, 2016). Oral benfotiamine has shown to have a much higher bioavailability than oral thiamine. Also, benfotiamine maintains the active form of thiamine (ThDP) for longer periods than hydrosoluble thiamine (Gibson, 2013).

Does benfotiamine cross the blood-brain barrier?

There is currently no evidence that it does. After intestinal absorption, benfotiamine enters the bloodstream as S-benzoylthiamine, which is converted to free thiamine in the erythrocytes and liver. Benfotiamine is not lipophilic, does not seem to cross the blood-brain barrier and is unable to diffuse across cell membranes. However, S-benzoylthiamine can cross plasma membranes by simple diffusion (Volvert, 2008; Sambon, 2021).

Can benfotiamine be administered intramuscularly?

Oral administration of benfotiamine is a more efficient route than parenteral route as benfotiamine needs to be dephosphorylated first by the intestinal alkaline phosphatases to the liposoluble S-benzoylthiamine (Volvert, 2008; Balakumar, 2010; Bozic, 2015).

So, if benfotiamine is better absorbed, are thiamine levels in the cells higher after benfotiamine administration than after thiamine administration?

In mice, benfotiamine administration is followed by a rapid increase in thiamine levels in the blood and liver. In a study in rats, benfotiamine administration resulted in a 100% increase in total plasma thiamine leveIs (Portari, 2013). In the red blood cells, thiamine levels increased 4-fold after thiamine and 25-fold after benfotiamine - compared with the rats which had not received thiamine or benfotiamine (Portari, 2013). In liver, thiamine increased by 60%.

If benfotiamine increases thiamine concentrations in the cell, what happens to the enzymes which depend on it?

We have seen that key enzymes in the cell depend on ThDP as a cofactor. Transketolase is a key thiamine-dependent enzyme of the pentose phosphate pathway (PPP).

What is the pentose phosphate pathway (PPP)?

The PPP is a metabolic pathway which is crucial to neurons as it results in anti-oxidant activities, in addition to biosynthesis processes. Neurons are very sensitive to oxidation.

What are the main functions of the PPP?

The PPP generates NADPH and ribose-5-phosphate which are critical for cell survival. NADPH is an important reducing agent. It helps also to regenerate reduced glutathione, which protects the cell from oxidative damage and helps to maintain the reduction-oxydation (redox) homeostasis. Reduced glutathione levels are decreased in the brains of persons with Parkinson’s (Wei, 2020).

As a key ThDP-dependent enzyme in the PPP, transketolase then plays an important role in the regulatory mechanisms of oxidative stress.

What controls the PPP?

The PPP departs from glucose-6-phosphate (G6P), at the beginning of glycolysis. It diverts metabolism from the glycolysis pathway – which produces energy in the form of ATP – to the PPP – which results in biosynthesis and anti-oxidant activities (Ge 2020; Wilkinson, 2020).

Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the PPP. This means that G6PD regulates the flow of G6P entering the PPP.

Is the activity of G6PD altered in Parkinson’s disease?

The activity of G6PD has been found to be upregulated in microglia, in in vitro and in vivo Parkinson’s models.

Does the PPP then work normally in Parkinson’s disease?

The PPP function is altered in Parkinson’s. G6PD increased activity results in PPP dysfunction.

What happens if the PPP does not function properly?

If the PPP function is altered, as in Parkinson’s, oxidative stress may ensue, resulting in neuronal damage. The inhibition of the PPP has caused dopaminergic cell deaths in animal models (Dunn, 2014).

G6PD upregulation generates excessive NADPH and leads to overproduction of reactive oxygen species - ROS (Tu, 2019), which results in neurotoxicity. Increased NADPH production has been described in the putamen (a brain region affected in Parkinson’s) of late-stage cases (Dunn, 2014).

The inhibition of G6PD in Parkinson’s models is able to reduce microglia activation and neuroinflammation and is associated with reduced loss of neurons.

Does benfotiamine correct PPP dysfunction?

Many authors believe that benfotiamine activates transketolase. By activating transketolase and the PPP, benfotiamine would prevent oxidative stress and DNA damage. Transketolase drives the precursors of AGEs to the PPP, reducing their production and buildup.

What are AGEs?

Advanced glycation end products (AGEs), also known as glycotoxins, are products generated in the cell which have a strong oxidant effect and can cause increased oxidant stress and inflammation. Under certain conditions, AGEs may accumulate in the cell.

What happens in diabetic neurologic complications?

Hyperglycemia in diabetes causes an increased production and rapid accumulation of AGEs (Balakumar, 2010) with increased utilization of NADPH (Lei Pang, 2020), which plays a key role to maintain the redox homeostasis. This is thought, among other factors, to contribute to diabetes-associated complications (Balakumar, 2010), including neuropathy.

AGEs build-up (Schmid, 2008: Balakumar, 2010) causes cell damage. Possible mechanisms include the activation of macrophages and endothelial cells - triggering an inflammatory response - and enhancing oxidative stress which impairs vascular tone (Balakumar, 2010; Lei Pang, 2020).

Transketolase has been shown to prevent vascular cell dysfunction due to hyperglycemia (Ge, 2020).

What does benfotiamine do?

In diabetes, benfotiamine administration increases intracellular concentration of thiamine and ThDP (Bashir, 2024), stimulates transketolase activity – causing a drop in AGE concentrations (Coy, 2005) and blocks hyperglycemic damage, contributing to prevent or reverse diabetic complications, including neuropathy (Hammes, 2003).

Randomized, placebo-controlled, double-blind trials in patients with diabetic polyneuropathy have consistently shown that benfotiamine, at dosages up to 600 mg/day, improves neuropathy symptoms and has particularly evident effects on pain (Stracke, 1996; Winkler, 1999; Haupt, 2005; Stracke, 2008). As parameters such as HbA1c and fasting blood glucose have remained unchanged, such improvements do not appear to be linked to an effect of benfotiamine on glucose metabolism but rather to other mechanisms.

What have studies on benfotiamine shown in diabetic neuropathy?

Clinical studies in diabetic patients with neuropathy have to date consistently shown that benfotiamine:

- Causes an improvement in symptoms, which is more evident at higher than lower doses (600 Vs 300 and 150 mg daily dose) and with a treatment of longer duration.

- Has effects particularly evident on pain.

- Leads to improvements which are not related to glucose metabolism, as parameters such as HbA1c and fasting blood glucose have remained unchanged.

So, by enhancing the cell reducing capacity and protecting against oxidative stress, does benfotiamine exercise neuroprotective effects?

Benfotiamine has shown to have neuroprotective effects. It is commonly believed that symptoms are linked to decreased activity of enzymes which depend on ThDP, the active form of thiamine (Volvert, 2008; Bettendorff, 2023). However, it has recently been suggested that benfotiamine may act also through coenzyme-independent antioxidative and anti-inflammatory effects (Bettendorff, 2023).

What is the rationale for benfotiamine non-coenzyme-dependent mechanisms?

We have seen that benfotiamine administration is followed by a rapid increase in thiamine levels in the blood and liver. But the situation is different in the brain. In a study in which mice were given benfotiamine for 14 days, thiamine, thiamine monophosphate (ThMP) and thiamine diphosphate (ThDP) levels did not increase in the brain (Volvert, 2008). Many other studies have found no increase of ThDP after benfotiamine administration (Pan, 2010; Tapias, 2018; Vignisse, 2017). So, it has been suggested that this may not be the main mechanism through which benfotiamine work and that benfotiamine antioxidant and anti-inflammatory effects may be due to mechanisms other than its coenzyme-dependent functions.

Is there any evidence that benfotiamine improves symptoms, despite a lack of increase in ThDP levels in the brain cells?

Benfotiamine has a strong antioxidative effect and enhances the antioxidative system in the cell. In animal models of Parkinson’s, the daily administration of benfotiamine for 42 days had antioxidant and anti-inflammatory effects and significantly improved motor and nonmotor symptoms, including behavior and balance, and dopamine levels in the mid-brain (Bushra, 2024).

Benfotiamine has been shown to protect against diabetic neuropathy in pre-clinical and clinical studies, to have neuroprotective effects in animal models of neurodegenerative diseases and on mild cognitive impairment in people with mild/moderate Alzheimer’s disease in clinical trials. A potential role in neurodegenerative diseases has been proposed.

What are the factors which are involved in neurodegeneration?

Glucose metabolism impairment, activated microglia, oxidative stress and neuroinflammation are currently believed to play a major role in neurodegeneration, including in Parkinson’s disease.

If benfotiamine does not increase ThDP levels, how can it contrast these factors which are likely to interfere with cell functions, causing cell death and symptoms?

Benfotiamine has shown in cell cultures and animal models to have antioxidant and anti-inflammatory properties.

Recently, there has been interest in the still unexplored non-cofactor role that thiamine metabolites such as thiamine triphosphate and adenosine thiamine triphosphate may have in conditions in which there is thiamine deficiency such as Alzheimer’s (Gibson, 2013; Sambon, 2021).

Interestingly, benfotiamine protective effects on oxidative stress, inflammation and AGE described in some studies have occurred without an increase in ThDP in the brain (Pan et al., 2010; Vignisse, 2017), suggesting the involvement of other mechanisms.

Microglia are thought to be involved in neurodegeneration. What role do microglia normally have in the brain?

Microglia in the brain play many and complex roles. Among them, microglia have immune response functions - secreting anti-inflammatory cytokines; tissue-repair capabilities - releasing neurotrophic factors; and act as macrophages, removing dead or damaged neuron cells, alpha-synuclein, microbes and what appears to be a threat to the brain. Microglia communicate with other types of cells in the brain and interact with infiltrating immune cells in peripheral inflammation. They are also involved in the regulation of synaptic function and elimination of synapses (Gao, 2023).

Then, microglia are another factor involved in neurodegeneration…

There is increasing evidence that activation of microglia may play a role in neurodegenerative diseases (Gao, 2023). Microglia are able to cause inflammation, releasing cytokines and chemokines, and, through NADPH oxidase, produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Block, 2007; Tu, 2019), which may be an important pathogenetic mechanism in Alzheimer’s and Parkinson’s, inducing damage to neurons (Metodiewa, 2000).

In mouse models and human tissue autopsy, reactive microglia have been found near amyloid plaques or α-synuclein deposits in various brain regions (Gao, 2023).

Activation of microglia with overproduction of ROS and RNS and impaired oxidative metabolism are also thought to play an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer’s (Ke, 2004; Uttara, 2009). There is evidence of oxidative stress in the brain in animal models which is already present before plaques develop. It is known that the central nervous system is particularly vulnerable to it given its high demand for energy and oxygen utilization (Praticò, 2001).

Are microglia activated in Parkinson’s disease?

Microglia are activated in Parkinson’s (Edison, 2013). Microglia have been found activated in in vitro Parkinson’s models and in the substantia nigra of in vivo Parkinson’s models (Tu, 2019), with buildup of inflammatory mediators in autopsy brain tissue. Activation occurs early in Parkinson’s and seems to persist as disease progresses, even if the initial event that caused it ceases to exist (Imamura, 2003; Hald, 2007).

Reactive microglia with buildup of inflammatory mediators have been observed in autopsy brain tissue in the substantia nigra of persons with Parkinson’s.

What happens when microglia are activated?

Cytokines released by activated microglia may change from neuroprotective to neurotoxic during Parkinson’s progression. The pro-inflammatory substances released can cause neuroinflammation, which over time would contribute to the development of Parkinson’s (Gao, 2023). Increased cytokines levels have been found in the serum and cerebro-spinal fluid (CSF) of persons with Parkinson’s and in neuroinflammation caused by alpha-synuclein (Gao, 2023). In peripheral inflammation, infiltration of immune cells turns microglial into a pro-inflammatory phenotype, contributing to neurodegeneration (Hirsch , 2003).

Alpha-synuclein aggregates in Parkinson’s, attracting microglia to the sites and turning them into the pro-inflammatory phenotype, which results in increased production of inflammatory cytokines and the generation of free radicals. Neuroinflammation caused by alpha-synuclein has an important role (Zhang, 2005), as it has been seen that it may occur even before the loss of dopaminergic neurons in Parkinson’s and may in turn cause further microglial activation, perpetuating the effect. Alteration of phagocytosis by microglia may lead to neuroinflammation and neurodegeneration (Gao, 2023).

Is there any evidence that glucose metabolism is reduced? How does it relate to activation of microglia in neurodegenerative diseases, including Parkinson’s disease?

It has been observed that glucose metabolism in cortical areas is reduced in Parkinson’s and this is inversely associated with microglia activation since early in the disease. In a study carried out in persons with Parkinson’s using imaging techniques (magnetic resonance imaging – MRI - and positron emission tomography – PET - scans), Edison et al. found significant microglia activation in cortical areas of the brain in Parkinson’s compared with controls and this correlated with cognitive impairment. The Authors have hypothesized that activated microglia may play an important role in the pathogenesis of dementia in Parkinson’s (Edison, 2013).

In a study in persons who had Alzheimer’s, mild cognitive impairment (MCI) or Parkinson’s – with and without dementia, Fan et al. found a negative correlation between increased microglial activation and reduced glucose metabolism in those with Alzheimer’s, MCI and Parkinson’s and a positive correlation between amyloid and microglial activation in persons with Alzheimer’s and those with MCI. Microglial activation in cortical areas was negatively correlated with cognitive impairment in both persons with Alzheimer’s and Parkinson’s with dementia (Fan, 2015).

Does benfotiamine reduce activation of microglia?

Benfotiamine has been shown to reduce microglia activation. Benfotiamine also enhances glutathione synthesis in activated microglia, protecting the cell against oxidant insults (Bozic, 2015; Lu, 2009, 2013).

We have seen the role that activated microglia may have in neurodegenerative diseases. What about intestinal microbiota?

Intestinal microbiota may play an important role in influencing microglia functions (Erny, 2015). The use of antibiotics, modifying the microbiota, has resulted in changes in microglial function. Bacterial fermentation in the gut produces SCFAs.

Which effects do the increased production of short-chain fatty acids (SCFAs) in the intestine have?

SCFAs have been reported to have many important beneficial effects, including, among others, anti-inflammatory, immunoregulatory and neuroprotective effects (Xiong, 2022).

SCFAs are important mediators of the gut–brain axis. They would inhibit the production of pro-inflammatory mediators while fostering the production of anti-inflammatory mediators, in this way inducing anti-inflammatory effects. Through the gut-brain axis, this could result in reduced inflammation and oxidative stress in the brain (Bettendorff, 2023).

Does benfotiamine affect the microbiota?

A significant amount of benfotiamine is converted into thiamine in the intestine. The unabsorbed amount of thiamine could modulate intestinal microbiota and, as we have seen, potentially reduce inflammation and oxidative stress in the brain.

What about benfotiamine effects in Alzheimer’s disease?

In pre-clinical studies on Alzheimer’s, benfotiamine has improved glucose metabolism, protected against oxidative damage and AGEs, reduced inflammation, protected against the formation of neurofibrillary tangles and phosphorylated tau levels in cortical areas, improved memory and survival. In clinical trials, benfotiamine has improved mild cognitive impairment or mild dementia due to Alzheimer’s. These findings are promising, although require further confirmation.

How safe is benfotiamine?

Benfotiamine has been reported in clinical trials to be well tolerated and with no adverse effects, except for an increase in blood pressure in one study (Fraser, 2012).

Looking at the evidence so far, can persons with Parkinson’s start using benfotiamine?

No clinical studies on benfotiamine in Parkinson’s have been carried out to date. Until randomised, placebo-controlled, double-blinded trials are conducted in people with Parkinson’s confirming benfotiamine safety, dosage and efficacy, benfotiamine can not be recommended for use in Parkinson’s disease.

Is there any issue with benfotiamine dosage in Parkinson’s disease?

The studies which have been conducted so far with benfotiamine in different conditions have used a fixed dose of benfotiamine for each participant. However, it has been reported that in high-dose thiamine therapy in Parkinson’s the dose of thiamine needs to be carefully adjusted to the individual person through a “trial and error” approach. The need to tailor the dose to each person may be related to the varying proportion of surviving neurons and the rate at which the cells can recover in a person with Parkinson’s. This is most likely to differ from person to person. It is not known whether the same approach of a dose tailored to each person should apply also to benfotiamine in Parkinson’s.

What can be concluded?

It can be concluded that, with its activation of transketolase and by reducing microglia activation, oxidative stress and inflammation, benfotiamine represents an attractive, potential treatment option for testing in clinical trials in Parkinson’s.

This Q&A post on benfotiamine is based on the b1parkinsons.org document “Thiamine forms: Benfotiamine”, which is part of the b1parkinsons.org technical basis series on the rationale for the High-dose Thiamine (HDT) protocol in Parkinson’s disease, available to health care providers in the website section “Member area”, reserved for registered health professionals. A complete list of references is provided at the end of that document.


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