Drug Repurposing Update #2 – Tanganil ® (Acetyl-Leucine) – Potential Mechanisms of Drug Action 

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Medical Disclaimer: Exemplifying the SRF value of transparency, this article is here to make families aware of what is happening. The information provided is for general informational purposes only and is not intended as, nor should it be considered a substitute for, professional medical advice. Although it may be helpful to share with your clinicians, do not use the information on this page for diagnosing or treating any medical or health condition. If you have, or suspect you have, a medical problem, promptly contact your professional healthcare provider. See full disclaimer here.

See Update #1 here.


Acetyl-leucine is a drug that was identified as a potential drug repurposing candidate for treatment of SynGAP1-related disorder. SRF’s previous post on the potential use of acetyl-leucine for the management of SynGAP1-related disorder symptoms has generated interest within the broader rare disease community. 

To provide information to parents and providers wanting to learn more about acetyl-leucine, we’ve prepared this short review of proposed mechanisms of drug action. This is the result of a detailed review of publications by the SRF Science team; these hypotheses are informed by these publications. There are several potential mechanisms (or combinations thereof) by which acetyl-leucine may be alleviating neurological impairments that have been reported in the literature. We describe three potential mechanisms below, first in broad terms and then in greater detail, however additional experimental work is needed to determine the exact mechanisms. Additionally, we provide a list of clinical studies demonstrating the effect of acetyl-leucine or N-acetyl-L-leucine treatment in humans to highlight the known applications of this drug.

Note: Leucine exists in two forms: D-leucine and L-leucine. These forms are mirror images of each other, much like your left and right hands. Acetyl-leucine is created when an acetyl group (a small chemical group made up of two carbon atoms, three hydrogen atoms, and one oxygen atom) is added to leucine. This modification can occur on either the D or L form of leucine. The combination of N-acetyl-L-leucine and N-acetyl-D-leucine is called acetyl-leucine. Pharmaceutical grade acetyl-leucine and N-acetyl-L-leucine are not yet globally available. Acetyl-leucine, under the trade name Tanganil® (Pierre Fabre Laboratories), has been used over-the-counter to treat vertigo in France for over 65 years1.

Broad description:  

Neurological disorders are characterized by several imbalances in the brain, including decreased pH and increased lactate levels, impaired removal of cellular waste, and altered energy use. Acetyl-leucine may help correct these imbalances in the following ways.

  1. Acetyl-leucine may balance pH levels in the brain by helping cells to get rid of lactate, which in high concentrations can cause low pH levels. Acetyl-leucine enters cells by a transport protein, called MCT1. When MCT1 transports one molecule of acetyl-leucine into the cell, it may also transport one molecule of lactate out of the cell. This exchange of charged molecules helps to restore the brain to a normal pH. 
  2. Once acetyl-leucine is inside neurons, it can help regulate how cells balance growth and clean up damaged parts. Acetyl-leucine inhibits a protein complex called mTORC1, which promotes the process of autophagy, where cells break down and recycle their components. This can help remove damaged or misfolded proteins, and reduce inflammation in the brain.  
  3. Acetyl-leucine may also enhance brain activity by improving how cells use glucose for energy. In patients with cerebellar ataxia, acetyl-leucine has been shown to improve glucose usage in certain areas of the brain, leading to better balance and coordination in some individuals.

While the exact mechanisms of how acetyl-leucine works are still being studied, its potential benefits include balancing brain pH, enhancing cellular cleanup, reducing inflammation, and boosting energy metabolism. Researchers are continuing to explore its effects in various brain conditions to better understand its therapeutic potential.

Detailed description:

HYPOTHESIS #1: Transport of acetyl-leucine into a cell may transport lactate out of the cell, alleviating a pH imbalance in the brain.  

While L-leucine is a natural and common amino acid, the chemical modification of L-leucine to make acetyl-leucine changes its properties and biological functions. Acetylation of L-leucine allows acetyl-leucine to enter neurons and other cells more efficiently by a different route1. L-leucine is a charged molecule at all physiologic pH ranges; it therefore requires active transport across cell membranes. Active transport occurs when a transporter protein in the cell membrane binds to a target molecule, in this case L-leucine, and moves it from one side of the cell membrane to the other (Figure 1, left). The L-type amino Acid Transporter (LAT1) is known to transport L-leucine and other large essential amino acids into cells2. Acetyl-leucine is uncharged at low pH and can enter cells through passive diffusion in the stomach. Passive diffusion occurs when a molecule can enter a cell directly, without a transporter protein. At higher pH ranges, acetyl-leucine enters cells through active transport. 

Acetyl-leucine neither binds nor blocks LAT11,3. Instead, acetyl-leucine has been shown to be transported by the organic anion transporters, OAT1 and OAT3, and the monocarboxylate transporter type 1 (MCT1)1. MCT1 transports several key monocarboxylates across cell membranes, including lactate, pyruvate, ketone bodies and acetate. A monocarboxylate is a type of organic molecule that contains one carboxylic acid group (-COOH) in its structure. MCT1 can transport monocarboxylates in two different ways4,5. It can function through a proton-linked cotransport mechanism, in which one monocarboxylate and one proton are transported across the membrane in the same direction. This type of transport can occur as a substrate influx into the cell or efflux out of the cell, depending on the substrate concentrations and pH gradients across the plasma membrane. MCT1 can also function as a bidirectional exchanger, by exchanging one substrate for another across the plasma membrane without the movement of a proton6. In this way, MCT1 can function like a revolving door, as it lets one molecule into the cell it also lets one molecule out of the cell. MCTs are ubiquitously distributed in the body7. MCT1 is notably at high concentrations in muscle tissue, brain, red blood cells, liver, kidney, intestinal epithelium and the retina. Additionally, MCT1 is expressed at the blood brain barrier, in the endothelial cells of the cerebral blood vessels8,9. Due to its broad distribution and potential delivery to the central nervous system, MCT1 is a target for drug development10. MCT1 is a known transporter of several drugs, including salicylate and valproic acid, which are monocarboxylate derivatives11.The exchange mode of MCT1 transport could be one mechanism in which acetyl-leucine exerts its therapeutic effects1. As acetyl-leucine is transported into the cell, the metabolic monocarboxylate end product lactate could be transported out (Figure 1, right). Accumulation or increased levels of lactate in the brain have been reported for several neurological disorders, including Parkinson’s, Alzheimer’s, Huntington’s, major depressive disorder, anxiety, bipolar disorder, schizophrenia, as well as in stroke and traumatic brain injury12. For several of these conditions, accumulation of lactate lowers the brain pH and subsequently affects the release of neurotransmitters and neuronal activity13–15. Cells with elevated lactate levels could enhance the uptake of acetyl-leucine through an exchange mechanism; this process would allow for increased delivery of the drug to cells experiencing metabolic dysfunction1. Therefore, as MCT1 exchanges acetyl-leucine and lactate it may help to rebalance the pH of the brain.

Figure 1. Transport of molecules across the cell membrane. Left) Small, unchanged molecules can pass directly through the cell membrane by passive diffusion. Large or changed molecules must be transported by a membrane transporter protein in a process that requires energy (ATP). Right) The monocarboxylate transporter type 1 (MCT1) actively transports molecules across the cell membrane using an exchange mechanism, one molecule goes into the cell and another molecule goes out of the cell. MCT1 transports acetyl-leucine into the cell and transports lactate out of the cell. Many neurological conditions are characterized by a low pH in the brain. When acetyl-leucine (negatively charged at neutral pH) and lactate (positively charged at neutral pH) are exchanged, the imbalanced pH in the neurons is restored.

HYPOTHESIS #2: Acetyl-leucine may increase cellular autophagy and reduce neuroinflammation.

L-leucine activates mTORC1 (Figure 2). The metabolic derivative of leucine, known as acetyl-coenzyme A (AcCoA), has been shown to positively regulate mTORC1 by facilitating the acetylation of an important protein, Raptor16,19. Conversely, acetyl-leucine has been shown to inhibit or negatively regulate the mTORC1 in a mechanism similar to that of rapamycin17. The concentrations of these two compounds in the cell therefore direct the cell to focus on either anabolic (building up complex molecules and tissues) or catabolic (breaking down and recycling damaged molecules) processes. The proper balance of catabolic and anabolic processes are important for health, so chronic activation or inhibition of mTORC1 can lead to disease. Once inside the cell, acetyl-leucine has been shown to be metabolized to L-leucine1. Therefore it is possible that acetyl-leucine initially inhibits mTORC1, promoting autophagy and allowing neurons and other cells to eliminate damaged or misfolded proteins, in a process that is self-limited by its metabolic product, leucine.

Dysregulation of autophagy has been shown to be associated with epilepsy20,21. Restarting stalled autophagy has been a proposed therapeutic approach for neurological disorders, including Niemann-Pick disease22. N-acetyl-L-leucine has been shown to upregulate autophagy in preclinical studies23. In mice with controlled cortical impact induced experimental traumatic brain injury (TBI), N-acetyl-L-leucine treatment led to an increase in autophagy. This was demonstrated as a reduction in accumulation of autophagosome markers in cortical tissue of treated mice as compared to controls. Increase in autophagy was associated with a reduction in neuronal death, reduced expression of proinflammatory cytokines, and ultimately a significant improvement in motor and cognitive outcomes23. Therefore, acetyl-leucine inhibition of the mTORC1 pathway may increase autophagy, resulting in removal of misfolded or damaged proteins and reduced neuroinflammation.

Figure 2. Regulation of the mechanistic Target of Rapamycin Complex 1 (mTORC1) by L-leucine and acetyl-leucine. Left) L-leucine activates mTORC1, resulting in cell growth. Acetyl-leucine inhibits mTORC1, resulting in autophagy. The balance of intracellular L-leucine and acetyl-leucine regulate mTORC1 activity. Metabolism of acetyl-leucine to leucine eventually curtails mTORC1 inhibition in favor of cell growth and proliferation. Right) Autophagy is a process by which misfolded proteins and other unnecessary components of the cell are degraded and recycled. Misfolded proteins are engulfed by a phagophore which develops into an autophagosome then fuses with the lysosome where the contents are broken down for reuse. Increased autophagy results in reduced inflammation of the brain.

HYPOTHESIS #3: Acetyl-leucine may activate glucose metabolism and enhance brain activity.

Once acetyl-leucine enters cells it can be converted to L-Leucine which can be utilized in metabolism1. Leucine has many important functions in cells, including metabolic and regulatory roles in neurons24. Leucine can function as an alternative energy source and has been shown to improve glucose metabolism25,26. Altered or dysfunctional energy metabolism in the brain have been shown for varying neurological conditions, including Alzheimer’s disease27, stroke, traumatic brain injury28 and epilepsy29. Energy modulation may overcome several neurological impairments.

In patients with cerebellar ataxia, a disorder that manifests as a lack of muscle control during voluntary movements, acetyl-leucine has been shown to impact the central vestibular compensatory processing of the brain30. Vestibular compensation is a complex process by which the brain adapts to changes in the inner ear following vestibular injury or dysfunction, aiming to restore balance and normal function. Whole-brain imaging studies with patients with cerebellar ataxia have shown that acetyl-leucine treatment activates or increases glucose usage in the somatosensory (postcentral), visual (temporo-parietal-occipital cortex, primary and secondary visual areas, V5, and the precuneus), and secondary vestibular (middle/superior temporal gyrus, anterior insula)30. Conversely, acetyl-leucine treatment was shown to deactivate or reduce glucose usage in the cerebellum (Figure 3). However, not all individuals responded to acetyl-leucine treatment, with 12 out of 20 individuals (60%) demonstrating significant improvements in ataxia, which correlated with altered glucose metabolism patterns in the brain30.

While acetyl-leucine has been shown to accelerate vestibular compensation in animals following unilateral labyrinthectomy, a surgical procedure for the management of poorly compensated unilateral peripheral vestibular dysfunction, it has shown only minor effects on normal vestibular function31. Intracellular recordings from vestibular neurons showed the response to acetyl-leucine was dependent on the cell’s resting membrane potential. Acetyl-leucine has been shown to act on abnormally hyperpolarized and/or depolarized vestibular neurons by restoring membrane potential to normal values31. Therefore, acetyl-leucine may serve to balance energy and neuronal function within the brain.

Figure 3. Acetyl-leucine treatment modulates glucose and energy usage in the brain. Acetyl-leucine treatment in patients with cerebellar ataxia resulted in modified glucose metabolism in the brain. Increases in glucose metabolism were observed in visual and vestibular cortices, shown in red. Decreased glucose metabolism was observed in the cerebellum, shown in blue. This indicates increased sensory functioning and enhanced compensatory processes. Reconstructed from Becker-Bense, et al, 202330. All figures were created using BioRender.com.

Studies demonstrating the effect of acetyl-leucine or N-acetyl-L-leucine in humans

The following table includes a review of published studies evaluating the effects of either acetyl-leucine or N-acetyl-L-leucine in humans to demonstrate the range of potential clinical applications.

ArticleDiseaseAge of PatientDrugDose g/dayNegativeResultsPositive Results
Acetyl-DL-leucine in cerebellar ataxia ([18F]-FDG-PET study): how does a cerebellar disorder influence cortical sensorimotor networks? (2023)30.Cerebellar AtaxiaAdultNAL4–5 40% of patients did not respond to treat- mentImprovement in cerebellar hypometabolism and sensorimotor hypermetabolism in responders
Safety and Efficacy of Acetyl-DL-Leucine in Certain Types of Cerebellar Ataxia: The ALCAT Randomized Clinical Crossover Trial (2021)32Cerebellar AtaxiaAdultNAL5+No adverse eventsWell-tolerated, no difference as compared to placebo
Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series (2013)33.Cerebellar AtaxiaAdultNAL5No adverse eventsSignificant improvements in QOL, and coordination
Efficacy and safety of N-acetyl-L-leucine in patients with ataxia telangiectasia: A randomized, double-blind, placebo-controlled, crossover clinical trial (2024)34.Ataxia TelangiectasiaChildNALL1-4No adverse eventsNo significant effects on ataxia symptoms but improved nausea and constipation
The Effect of N-Acetyl-DL-Leucine on Neurological Symptoms in a Patient with Ataxia-Telangiectasia: a Case Study (2023)35.Ataxia TelangiectasiaChildNALL4Initial nausea and constipation (first week only)Improved coordination, enhanced QOL in physical, emotional, social, and school functions
Effects of Acetyl-DL-Leucine on Ataxia and Downbeat-Nystagmus in Six Patients With Ataxia Telangiectasia (2022)36.Ataxia TelangiectasiaChild – AdultNAL3-5No adverse eventsImprovement in cerebellar ataxia and ocular stability
Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C (2024)37.Niemann-Pick Disease Type CChildNALL2-4No adverse eventsSignificant reduction in neurological signs and symptoms. Improved ataxia and QOL
Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C (2022)38.Niemann-Pick Disease Type CChild – AdultNALL≥13y = 4g; <13 = <4gNo adverse eventsStatistically significant improvement in symptoms, functioning, and QOL
Acetyl-dl-leucine in Niemann-Pick type C: A case series (2015)39.Niemann-Pick Disease Type CYoung adultsNAL3-5Transient dizziness: 1 patientImprovement in cerebellar symptoms and QOL
Beneficial effect of N-acetyl-DL-leucine on cognitive function, emotional well-being and QoL in a mentally healthy elderly person (2023)40.AgingElderlyNALNANoneImproved cognitive function, emotional well-being, and QOL
An anecdotal report by an Oxford basic neuroscientist: effects of acetyl-DL-leucine on cognitive function and mobility in the elderly (2016)41.AgingElderlyNALNANo adverse eventsImprovement in cognitive function and mobility
Efficacy and Safety of N-Acetyl-l-Leucine in Children and Adults With GM2 Gangliosidoses (2023)42.Tay-Sachs and Sandhoff diseasesChild AdultNALL≥13y = 4g; <13 = <4gNo adverse eventsStatistically significant improvements in functioning and QOL
Sandhoff Disease: Improvement of Gait by Acetyl-DL-Leucine: A Case Report (2020)43.Sandhoff DiseaseChildNAL0.1 g / kgNo adverse eventsImprovement in gait
The Effects of N-Acetyl-L-Leucine on the Improvement of Symptoms in a Patient with Multiple Sulfatase Deficiency (2023)44.Multiple Sulfatase DeficiencyChildNALL3No adverse eventsImproved coordination, physical health, emotional function and QOL
Acetyl-DL-leucine in combination with memantine improves acquired pendular nystagmus caused by multiple sclerosis: a case report (2023)45.Multiple Sclerosis AdultNAL3-5No adverse eventsImproved oscillopsia and stance and gait
Acetyl-DL-leucine improves restless legs syndrome: a case report (2021)46.Restless Legs SyndromeAdultNALNANo adverse eventsMarked improvement in symptoms and sleep quality
Prophylactic treatment of migraine with and without aura with acetyl-DL-leucine: a case series (2019)47.Migraine with and without auraAdultNAL5No adverse eventsReduced frequency and severity of migraine attacks
Lack of benefit of acetyl-DL-leucine in patients with multiple system atrophy of the cerebellar type (2017)48Multiple System Atrophy – Cerebellar Type AdultsNALNANo adverse eventsNo significant benefit observed
Effects of acetyl-DL-leucine in vestibular patients: a clinical study following neurotomy and labyrinthectomy (2009)31.Vestibular disorders AdultNALNANo adverse eventsEased static vestibular syndromes; restored membrane potential of vestibular neurons towards normal values
Clinical or observational studies using acetyl-leucine (NAL) or N-acetyl-L-leucine (NALL) and their outcomes. QOL = quality of life.

Conclusion

The exact mechanism by which acetyl-leucine is mediating its therapeutic effect is still unknown. The mechanisms reviewed here may potentially contribute to the reported neurological improvement either individually or the mechanisms could be synergistic. Results of clinical studies demonstrate a wide range of applications for acetyl-leucine or N-acetyl-L-leucine in treatment of neurological conditions. However, the impact of acetyl-leucine treatment may also vary by individual, as demonstrated by the variable outcomes of treated individuals with cerebellar ataxia. 

SRF continues to work with and support several research teams to further investigate the effect of acetyl-leucine treatment in SYNGAP1-affected animal models and its mechanism of drug action. We continue to monitor the safety and drug effects of patients within the SYNGAP1 community who have decided to try this over-the-counter drug. This work has also created interest in acetyl-leucine treatment within the rare disease community. We are collaborating closely with a number of scientific advisors and other patient advocacy groups. The effects of acetyl-leucine are also being evaluated in preclinical studies for other neurological conditions.

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