Description

Sulbutiamine Nootropic Powder

 

 

 

CAS Number	3286-46-2
Other Names	Bisibutiamin, Arcalion, Bisibutiamine, Sulbutiamina, Sulbutiaminum, Bisibuthiamine, Vitaberin, O-Isobutyroylthiamine disulfide
IUPAC Name	[(E)-4-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-3-[[(E)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-(2-methylpropanoyloxy)pent-2-en-3-yl]disulfanyl]pent-3-enyl] 2-methylpropanoate
Molecular Formula	C₃₂H₄₆N₈O₆S₂
Molecular Weight	702.9
Purity	≥99% Pure (LC-MS)
Liquid Availability	30mL liquid (100mg/mL, 3000mg bottle)
Powder Availability	25 grams, 50 grams
Gel Availability	N/A
Storage	Store in cool dry environment, away from direct sunlight.
Terms	All products are for laboratory developmental research USE ONLY. Products are not for human consumption.

 

What is Sulbutiamine

Sulbutiamine is a synthetically developed compound composed of two thiamine molecules, bound together by sulfur. Sulbutiamine is known for its fat solubility as the lipophilicity of the compound allows it to be easily transported into the brain from systemic circulation due to its ability to cross the blood brain barrier. This increased bioavailability of the nootropic allows for onset of benefits and effects at a faster rate and potency than a single thiamine molecule. Current research regarding treatment with sulbutiamine focuses on the neuroprotective effects elicited by the compound related to onset of ischemia, diabetic neuropathy, and glutamatergic and dopaminergic transmission.

 

Main Research Findings

1) Treatment with sulbutiamine has been shown to elicit regulatory effects on cortical transmission of glutamine and dopamine in the brains of rats.

2) Sulbutiamine administration has been shown to improve diabetic neuropathy in animal models by regulating PKC/TLR-4/NF-kB signaling.

 

Selected Data

1) The research team of Trovero et al examined the effects of acute and chronic treatment with sulbutiamine and how it affects glutamatergic and dopaminergic binding sites in the prefrontal and cingulate cortices of rat brains. For the purpose of this study, male Sprague-Dawley rats weight between 200 and 250 grams were used. The animals were treated daily, for 14 days with 12.5 mg/kg of sulbutiamine administered via intraperitoneal injection in order to represent the chronic treatment experimental group. Following the last injection of sulbutiamine the rats were euthanized either 2 hours or 5 days later. In order to represent the acute treatment experimental group, rats were intraperitoneally injected with a single 12.5 mg/kg dose of sulbutiamine. Following administration of sulbutiamine the rats are euthanized either 15 minutes, 30 minutes, 1 hour, 4 hours, 12 hours, or 24 hours later [1].

After the animals were euthanized the brains were dissected and frozen prior to being cut at different levels to create several 20 uM sample slices of the prefrontal and cingulate cortices. The samples were then mounted on glass slides and stored until the day they were to be incubated with ligand. First, autoradiographic experimentation observing the activity of D1 dopaminergic, N-methyl-d-aspartate (NDMA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainate, were performed. In order to assess the activity of D2 dopaminergic binding sites, the sections were incubated with 50 mM of Tris-HCl buffer containing iodosulpride for 60 minutes. Unlabelled sulpiride was added next in order to evaluate non-specific binding, followed by washing with Tris-HCl buffer and exposure to ultrofilm for 10 days. Once the samples were fully developed densitometric analysis of autoradiographic films was performed in order to obtain measurements for binding quantification. This process was completed by transforming the autoradiograms into digitised diagrams using an image analyzer with 256 grey levels for each pixel. The values of the gray levels were then transformed into optical density via computer programming. The optical film densities were then converted to tissue ligand concentrations based on the densities of the overlying radiative standards and the activity of the radioligands [1].

Next, monoamine levels were estimated by euthanizing the rats 2 hours after a single dose of sulbutiamine was delivered, followed by dissection and freezing of the brain tissues. Frontal brain sections were sliced at 400 uM thick and included samples from the microtome, prefrontal cortex, nucleus accumbens, and the anterior cingulate cortex. The samples were maintained in 100 uL of perchloric acid containing ethylene diamine tetra-acetic acid, and 0.01% cysteine and sonicated. The samples were then centrifuged for 40 minutes and the resulting supernatants were purified on alumine micro columns and injected into a liquid chromatography C18 column that was calibrated using a solvent of sodium phosphate buffer, 1-octanesulfonic acid, triethylamine, ETA, NaH2PO4, and methanol. The solution was adjusted to a pH of 2.9 through the addition of phosphoric acid. From there the rate of injection was 1 mL/min and electrochemistry with a carbon electrode set at 0.65 V was performed to quantify levels of dopamine and 3,4-dihydroxyphenylacetic acid [1].

2) The research team of Ghaiad et al examined the effects of sulbutiamine on the progression of diabetic neuropathy in rats with induced diabetes. For the purpose of this study, 7-9 week old Wistar albino rats were utilized. The animals were allowed to acclimatize to the laboratory space for 2 weeks while they were housed 4 rats to a cage and maintained under standard laboratory conditions with ad libitum access to food and water. All animals were randomly divided into four different experimental groups including: a control group; a group that received an intraperitoneal injection of citric acid buffer followed by oral administration of PBS for 8 weeks in order to evaluate baseline values of the experimental parameters; a group orally administered 60 mg/kg of sulbutiamine for 8 weeks; and a group that received a single intraperitoneal injection of STZ after 1 hour of fasting [2].

72 hours after STZ injection was delivered, the fasting blood glucose levels were assessed. Blood glucose levels below 250 mg/dl were excluded while animals with blood glucose levels above 250 mg/dl were randomly divided into diabetic control groups and sulbutiamine-treated groups. The animals included in the sulbutiamine-treated group were orally administered 60 mg/kg of body weight suspended in PBS, for 8 weeks. The dose was given to the animals every day at 10 a.m. Following the experimental period body weight measurements were obtained while blood was collected from the retro-orbital plexus. Blood samples were separated through centrifugation and the separated aliquots of serum were stored for further analysis of urea, creatinine, and Kim-1 levels. The animals were then euthanized and their kidneys were dissected and weighed in order for further evaluation of various histological and biochemical parameters as well as immunohistological assays [2].

The blood biochemical assessments included a blood glucose measurement and serum kidney function tests. In order to measure blood glucose, blood was collected via tail vein puncture and passed through a GlucoDr Super sensor glucometer to estimate glucose levels. For kidney function testing, creatinine and urea assay kits were used to assess quantitative colorimetric determination of urea and creatinine levels in serum. Additionally, a Kim-1 ELISA kit was used to determine levels of serum kidney injury molecule 1 (Kim-1). Additionally, several renal biochemical assessments were performed by dissecting kidney tissue from rats included in different experimental groups. The samples were washed with saline and homogenized in a buffer containing sucrose, EDTA, and Tris-HCl. The homogenate were then centrifuged and the supernatant was used to estimate levels of renal malondialdehyde (MDA) and NF-kB using ELISA assay kits. In a similar manner to MDA and NF-kB levels, protein kinase C and TLR-4 concentrations in kidney homogenates were quantified [2].

After biochemical assessments were completed the research team performed histopathological examination. Kidney samples were fixed in 10% neutral buffered formalin, followed by processing in different grades of alcohol, and finally embedded in paraffin wax. Sliced sections were then stained with hematoxylin and eosin prior to light microscopy. Additional kidney sections were stained with PRS to assess for fibrosis through the samples. Histopathological changes were quantified by scoring inflammation on a scale of 0 to 4; scores were defined as follows: 0 = absent, 1 = mild focal, 2 = moderate focal, 3 = moderate multifocal, and 4 = severe and diffuse. Renal tubular damage was also scored on a 0 to 4 scale; scores were defined as follows: 0 = absent, 1 = mild degeneration, 2 = moderate degeneration, 3 = marked focal necrosis, and 4 = severe diffuse necrosis. Finally, renal fibroplasia was scored on a 0 to 4 scale; scores were defined as follows: 0 = absent, 1 = mild fibroplasia, 2 = moderate focal, 3 = marked local fibrosis, and 4 = severe diffuse fibrosis [2].

Kidney sections were then immunostained after being cut into adhesive slides. The slides were re-hydrated and incubated with the following antibodies: Mouse anti- IL-1, anti- TNF-alpha, and TGF-beta. Incubation took place for 12 hours followed by washing to TBH and hydrogen peroxide to block for endogenous peroxidases. HRP-labelled anti-mouse antibody and color development and detection via DAB-substrate kid were added to the slides next. Primary antibodies were then deleted in order to obtain negative control slides that were then examined using a BX43 light microscope and digital camera to quantify positive expression [2].

 

Discussion

1) When observing the dopaminergic and glutamatergic binding activity, the autoradiographs obtained by the research team from the rat brain sections incubated with different ligands at anteriority levels, were representative of both the cingulate cortex and the nucleus accumbens. That being said, densitometry was performed based on the findings of the autoradiographs and revealed that chronic treatment with 12.5 mg/kg of sulbutiamine resulted in a significant increase in the density of D1 dopaminergic binding sites in both the anterior cingulate cortex and the prefrontal cortex by 34% and 26%, respectively [1].

Additionally, 5 days after chronic treatment was complete there was a significant decrease in the density of kainate binding sites noted throughout the cingulate cortex and the nucleus accumbens by 36% and 28%, respectively. Similar results were noted through the striatum and the hippocampus. However, there were no remarkable changes in the density of D2 dopaminergic receptors, nor any of the other glutamatergic binding sites related to NMDA and AMPA subtypes [1].

When looking at acute administration of sulbutiamine there were no significant changes in the binding density of H-SCH 23390 nor iodosulpride. 15 minutes after sulbutiamine was administered, kainate binding sites experienced a decrease in density. In a similar manner, 1 hour after administration of sulbutiamine there was a decrease in the density of binding sites in the prefrontal cortex. These results were observed in the samples up to 24 hours after injection of the nootropic.

Furthermore, despite the presence of sulbutiamine metabolites in the brain there were no significant changes observed in the binding sites within the 2 hours following chronic treatment with sulbutiamine. That being said, the research team was able to exclude the possibility of sulbutiamine and/or the metabolites occupying the kainate binding sites. Additionally, there were no significant changes in the density of D1 or D2 dopaminergic and the kainate binding sites throughout the nucleus accumbens. DOPAC levels in the prefrontal cortex were shown to decrease by 30% following a single acute injection of sulbutiamine. Reduced levels of DOPAC indicate that there was also a decrease in the release of dopamine in the prefrontal cortex. Similarly, when compared to the control group of animals, DOPAC and dopamine levels reduced by 26% and 34%, respectively, throughout the cingulate cortex [1].

The researchers noted that the induced compensatory mechanisms present following chronic treatment with sulbutiamine may result in increased density of D1 dopamine receptors within 2 hours of chronic treatment. However, when sulbutiamine treatment is interrupted the induced compensatory mechanisms disappear, resulting in no modification of the D1 dopamine binding sites observed after 5 days. Acute administration of sulbutiamine was not sufficient to cause significant changes in D1 receptor density, indicating that changes of receptor sensitivity occur after chronic changes in dopaminergic transmission induced by the nootropic.

In terms of glutamatergic transmission, the researchers found that changes in kainate receptor density in the cortex suggests that sulbutiamine has the potential to modulate glutamatergic transmission. A direct effect on transmission is observed following the rapid decrease noted immediately following acute treatment with sulbutiamine. The results reported by the research team indicate that interactions between dopaminergic and glutamatergic transmissions within the prefrontal cortex have the ability to play a key role in the therapeutic effects elicited by sulbutiamine [1].

Figure 1: Changes in various glutamatergic and dopaminergic binding site densities throughout the prefrontal cortex, cingulate cortex, and nucleus accumbens following chronic treatment with sulbutiamine.

Figure 2: Changes in D1 and D2 dopaminergic and kainate binding site densities throughout the prefrontal and cingulate cortices following acute treatment with sulbutiamine.

2) The results of the study conducted by the research team of Ghaiad et al reported that when treated with a single dose of STZ, both body weight and fasting blood glucose levels were changed. When compared to normal control groups and groups treated with sulbutiamine, blood glucose levels were found to have increased following injection of STZ. When the test subjects were treated with sulbutiamine there was a significant reduction in fasting blood glucose levels compared to the group of rats with induced diabetes. In terms of body weight, treatment with STZ was shown to decrease body weight in the diabetic control group compared to the normal control group of rats. The sulbutiamine treated group of test subjects experienced an insignificant increase in body weight compared to the untreated group of subjects [2].

When looking at the effects of sulbutiamine on relative kidney weight in rats administered a dose of STZ, there was an increase in kidney weight in the diabetic-induced rats compared to control rats. When STZ was intraperitoneally administered to the animals, relative kidney weight nearly doubled in comparison to the animals in the control group and those treated with sulbutiamine. In the animals treated with sulbutiamine there was a notable decline in relative kidney weight when compared to the group of animals with induced diabetes [2].

Figure 3: Changes in A) fasting blood glucose levels, B) body weight, C) kidney weight, and D) relative kidney weight in animals with induced diabetes, following treatment with sulbutiamine.

When looking at the results of the various biochemical assessments performed by the research team, the diabetic control group experienced increased levels of serum urea, serum creatine, and Kim-1 by 1.9-fold, 2-fold, and 4-fold, respectively. That being said, when the diabetic-induced rats were treated with sulbutiamine, there was a significant reduction in serum urea by 39% and serum creatinine by 53%, in comparison to the diabetic control group of animals. In addition to creatinine and urea, Kim-1 levels were found to decrease by 55% when the test subjects were treated with sulbutiamine, in comparison to the diabetic control group. Furthermore, renal MDA content was found to increase by 3-fold in the diabetic control group in comparison to the normal control group and the group treated with sulbutiamine. These levels decreased by 52% when the animals were treated with sulbutiamine [2].

Figure 4: Changes in A) serum urea, B) serum creatinine, c) serum Kim-1, and D) renal MDA levels in test subjects with induced diabetes following treatment with sulbutiamine.

Treatment with sulbutiamine was then evaluated to determine its effects on NF-kB/TLR-4 pathways in rats injected with STZ. STZ administration resulted in a 4-fold increase in both NF-kB and TLR-4 levels in the kidneys compared to the normal control group and the sulbutiamine control groups. In the animals treated with sulbutiamine there was a 55% reduction in NF-kB and TLR-4 levels compared to animals with induced diabetes. Additionally, the researchers assessed effects of sulbutiamine treatment on renal PKC levels. The diabetic control group of rats experienced a 4.6-fold increase in PKC levels compared to the normal control group and sulbutiamine control group. However, when treated with sulbutiamine, the animals experienced a 62% decrease in PKC levels in comparison to diabetic control rats [2].

Figure 5: Changes in NF-kB, TLR-4, and PKC levels in diabetic rats following treatment with sulbutiamine

When looking at the effects of sulbutiamine on renal histopathological parameters, the research team reported that there were no histopathological changes detected in the control groups, while the sulbutiamine control group exhibited normal kidney functioning. In the diabetic control group, there was evidence of alternation in the renal cortex and medulla, as well as renal tubular degeneration and necrosis with presence of protein casts. Additionally, in the kidney sections obtained from diabetic test subjects mononuclear inflammatory cell infiltrations were identified in the renal cortex and medulla as well as renal fibroplasia with cystic dilation noted in the renal tubules.

When treated with sulbutiamine there was a marked increase in kidney function throughout the collected sections. However, the research team noted that there was very minor degeneration noted in very few of the sections with cystically dilated tubules. The diabetic control group was shown to exhibit increased inflammation, tubular damage, and renal fibroplasia, however, all of these scores were significantly lower when the animals were treated with sulbutiamine. There were also no statistically significant differences between the normal control group and the sulbutiamine control groups. Finally, PSR stained sections were observed to quantify the degree of renal fibrosis. There was an increase in the amount of fibrotic tissue present in the diabetic control group that was shown to reduce following treatment with sulbutiamine [2].

Figure 6: Changes in inflammation scores, tubular damage scores, and renal fibroplasia scores following treatment with sulbutiamine.

Finally, the researchers examined the immunohistochemical expression of TGF-beta 1, TNF-alpha, and IL-1 beta. The diabetic control group was found to experience a 4-fold increase in renal TGF-beta 1 levels in comparison to normal control and sulbutiamine control groups. When treated with sulbutiamine, the group of animals exhibited reduced levels of TGF-beta positive staining in comparison to the diabetic-induced animals. The diabetic animals also experienced elevated renal expression of IL-1 beta when compared to the control groups of rats. This expression was markedly reduced when treated with sulbutiamine in comparison to the diabetic control group of rats. The diabetic group also exhibited higher levels of TNF-alpha expression of more than 10-fold. Administration of sulbutiamine resulted in downregulation in TNF-alpha expression to normal levels when compared to the diabetic control group [2].

 

 

Figure 7: Changes in TGF-beta, IL-1 beta, and TNF-alpha expression following treatment with sulbutiamine

 

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citations

[1] Trovero F, Gobbi M, Weil-Fuggaza J, Besson MJ, Brochet D, Pirot S. Evidence for a modulatory effect of sulbutiamine on glutamatergic and dopaminergic cortical transmissions in the rat brain. Neurosci Lett. 2000 Sep 29;292(1):49-53. doi: 10.1016/s0304-3940(00)01420-8. PMID: 10996447.

[2] Ghaiad HR, Ali SO, Al-Mokaddem AK, Abdelmonem M. Regulation of PKC/TLR-4/NF-kB signaling by sulbutiamine improves diabetic nephropathy in rats. Chem Biol Interact. 2023 Aug 25;381:110544. doi: 10.1016/j.cbi.2023.110544. Epub 2023 May 22. PMID: 37224990.

What is Sulbutiamine?

Sulbutiamine is a synthetically developed compound composed of two vitamin B1 (thiamine) molecules, bound together by sulfur. Sulbutiamine is known for its fat solubility. The lipophilicity of the compound allows it to easily transport into the brain from systemic circulation at a greater rate and potency than a single thiamine molecule typically would. This observed phenomenon was further supported by the work of Bettendorff et. Al. The researchers examined how plasma thiamine levels would increase in rats when the subjects were administered either thiamine or sulbutiamine. The subjects were administered 52 mg/kg of sulbutiamine and 50 mg/kg of thiamine, daily, for two weeks. Results of the study reported that the rats receiving sulbutiamine exhibited 2.41 times higher levels of total circulating thiamine, thiamine diphosphate, and thiamine monophosphate than the rats being administered thiamine. The primary benefits of sulutiamine include enhanced cognition and improved neuroprotection, decreased fatigue, and the abiliy to effect circadian rhythm.

 

Effects of Sulbutiamine on Neuroprotection and Memory

Like most nootropic compounds, sulbutiamine has shown the potential to improve neuroprotection and various cognitive functions. A notable study conducted by Kwag et. Al examined the neuroprotective effect sulbutiamine had on hippocampal cells exposed to oxygen/glucose deprivatiohn (OGD). In order to create ischemic conditions in rats, OGD was initially induced alone, followed by combined exposure to both OGD and sulbutiamine. The combination of OGD and sulbutiamine led to a drastic increase in neuron viability, as well as the improvement of various electrophysiological properties. These results allowed the researchers to conclude that sulbutiamine exhibits neuroprotective effects that could combat ischemia-related cell deathm(https://pubmed.ncbi.nlm.nih.gov/22040892/).

Sulbutiamine has also shown potential in its ability to improve memory and retention. One of the first published studies regarding these effects was conducted in 1985 by Micheau et. Al. The researchers orally administered 300 mg/kg of sulbutamine to 14-16 week old mice for 10 days. Any memory improvement was measured by the subjects’ performance on an opertant task. The results reported that there was no significant difference in memory between acquisition groups. However, the mice showed a drastic improvement in retention which led to overall enhanced performance (https://pubmed.ncbi.nlm.nih.gov/4059305/).

A more recent study regarding the effects of sulbutiamine on memory included injecting mice with a sulbutiamine dosage of either 12.5 mg or 25 mg, daily, over the course of 9 weeks. Researchers BIzot et. Al collected baseline data by having the mice complete a DNMTS task prior to treatment. After the initial task was completed the mice began their 9-week treatment period. Following injection of sulbutiamine and a second DNMTS task, results reported that the treatment did not significantly improve memory but did enhance performance during object-recognition tests. Additionally, the researchers administered an NMDA antagonist known to cause amnesia. The placebo group experienced impaired memory while both the 12.5 mg and the 25 mg sulbutiamine groups had little to no memory impairments. The results of this study allowed the researchers to conclude that sulbutiamine is beneficial for both working and episodic memory (https://pubmed.ncbi.nlm.nih.gov/15951087/).

 

Effects of Sulbutiamine on Fatigue

Another primary benefit of sulbuitamine supplementation is the compounds ability to resolve chronic fatigue. An animal-based study conducted by Tiev et. Al examined how administration of sulbutiamine treats cases of chronic postinfectious fatigue (CPIF). The subjects were split into three groups: one receiving a placebo, one receiving 400 mg of sulbutiamine, and the last receiving 600 mg of sulbutiamine. The compound wad administered daily over a 28 day trial period. Results of the study found that both experimental groups showed significant improvement over the placebo group, however, there was no discernable difference in symptom reduction between the two experimental groups. The researchers concluded that in cases of CPIF, treatment with sulbutiamine can combat high instances of fatigue.

 

Effects of Sulbutiamine on Sleep

Further benefits of sulbutiamine administration was observed in primates by researchers Balzamo et. Al. When giving the subjects sulbutiamine in doses of 300 mg/kg, daily, for 10 days, the circadian rhythm of the primates showed signs of influence from the large dose of the compound. The researchers reported that administration of sulbutiamine led to increased wakefulness and phase 1 sleep without changing patterns of REM sleep. High levels of phase 1 sleep are important due to its ability to support memory, learning, and retention. Researchers were able to conclude that sulbutiamine shows the potential to regulate these phases of the sleep cycle, however more research should be conducted in order to determine the full effects of sulbutamine on circadian rhythm (https://pubmed.ncbi.nlm.nih.gov/7170385/).

The nootropics sold by Umbrella Labs are sold for laboratory research only. The description above is not medical advice and is for informative purposes only.

Sulbutiamine is sold for laboratory research use only. Terms of sale apply. Not for human consumption, nor medical, veterinary, or household uses. Please familiarize yourself with our Terms & Conditions prior to ordering.

 

 

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