Research

 

Research and Development

After 20 years of studying regulation of synaptic density and function at Stanford, MIT, and Tsinghua University, we were the first to identify intracellular magnesium as a critical second messenger controlling synaptic function and plasticity. 

Through molecular screening, Neurocentria identified a novel compound, L-Threonic Acid Magnesium Salt (L-TAMS; also published as Magnesium L-Threonate, MgT), that can selectively elevate intracellular magnesium at the synaptic terminal. In vivo, this compound increases synaptic density, function and plasticity; and improves learning and memory in young and old rodents.

Mechanistically, at least three pathways are modulated by L-TAMS.  Upregulation of NMDA receptor-mediated signaling underlies enhancement of synaptic plasticity.  Improvement of mitochondrial function both augments synaptic protein transport and decreases BACE-1 mediated Amyloid-beta deposition. 

 

L-TAMS treatment prevents and restores synaptic loss and alleviates cognitive impairment in AD-model mice.  

 

In human, early clinical trials suggest MMFS (clinical formulation of L-TAMS) treatment can improve learning and memory in elderly and Alzheimer's patients.

 

Publications

  • Discovery of activity-dependent principle underlying synaptic density regulation

(Liu and Tsien, Nature, 1995)

  • Importance of NR2B-NMDAR in synaptic plasticity and memory is elucidated from transgenic “Doogie” mice 

(Tang et al., Nature, 1999)

  • Neuronal intracellular Mg2+ identified as a 2nd messenger controlling synaptic plasticity and density

(Slutsky et al. Neuron, 2004) 

(Slutsky et al. Neuron, 2010) 

(Zhou and Liu. Mol Brain, 2015)

  • L-TAMS identified as drug candidate that increases structural / functional synapse density and promotes neurogenesis:

  1. Enhanced learning and memory in young and aged rats

(Slutsky et al., Neuron, 2010)

2. Prevented cognitive impairment in AD model mice

(Li et al., Mol Brain, 2014)

3. Increased NR2B-NMDAR pathway in rats

(Slutsky et al. Neuron, 2010) 

(Abumaria et al. J Neurosci, 2011)

4. Facilitated removal of fear memory and reduced anxiety

(Abumaria et al., J Neurosci, 2011) 

(Abumaria et al., Behav pharma, 2013)

5. Facilitated rejuvenation of the adult visual cortex, providing a new avenue to develop clinical therapies for adult      amblyopia

(Liu et al., Mol brain, 2015)

6. MOA is mediated by mitochondrial energy production enhancement and movement of Ca++ sensitive proteins to terminals

(Zhou et al., Mol brain, 2015)

7. L-threonate is critical for mechanism of action

(Sun et al., Neuropharmacology, 2016)

  • Positive results from L-TAMS in human trial in MCI patients (double-blind placebo-controlled)

(Liu et al., Journal of Alzheimer’s Disease, 2015)

  • Positive preliminary clinical trial results for L-TAMS tested in mild-moderate AD patients

(Wroolie, et al, Personalized Med Psych, 2017)

 

Mechanism of Action of Leading Drug Candidate MMFS

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