Dihydromyricetin ameliorates behavioral deficits and reverses neuropathology of transgenic mouse models of Alzheimer’s disease.
Neurochem Res. 2014 Jun;39(6):1171-81.
Liang J, Kerstin Lindemeyer A, Shen Y, López-Valdés HE, Martínez-Coria H, Shao XM, Olsen RW.
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA, [email protected]
Alzheimer’s disease (AD) is the leading progressive neurodegenerative disorder afflicting 35.6 million people worldwide. There is no therapeutic agent that can slow or stop the progression of AD. Human studies show that besides loss of cognition/learning ability, neuropsychological symptoms such as anxiety and seizures are seen as high as 70 and 17 % respectively in AD patients, suggesting dysfunction of GABAergic neurotransmission contributes to pathogenesis of AD. Dihydromyricetin (DHM) is a plant flavonoid and a positive allosteric modulator of GABAARs we developed recently (Shen et al. in J Neurosci 32(1):390-401, 2012 ). In this study, transgenic (TG2576) and Swedish transgenic (TG-SwDI) mice with AD-like pathology were treated with DHM (2 mg/kg) for 3 months. Behaviorally, DHM-treated mice show improved cognition, reduced anxiety level and seizure susceptibility. Pathologically, DHM has high efficacy to reduce amyloid-β (Aβ) peptides in TG-SwDI brain. Further, patch-clamp recordings from dentate gyrus neurons in hippocampal slices from TG-SwDI mice showed reduced frequency and amplitude of GABAAR-mediated miniature inhibitory postsynaptic currents, and decreased extrasynaptic tonic inhibitory current, while DHM restored these GABAAR-mediated currents in TG-SwDI. We found that gephyrin, a postsynaptic GABAAR anchor protein that regulates the formation and plasticity of GABAergic synapses, decreased in hippocampus and cortex in TG-SwDI. DHM treatment restored gephyrin levels. These results suggest that DHM treatment not only improves symptoms, but also reverses progressive neuropathology of mouse models of AD including reducing Aβ peptides, while restoring gephyrin levels, GABAergic transmission and functional synapses. Therefore DHM is a promising candidate medication for AD. We propose a novel target, gephyrin, for treatment of AD.
Alzheimer’s disease is the leading progressive neurodegenerative disorder characterized by loss of cognition, memory, and learning abilities, psychiatric disorders; pathologically irreversible loss of synapses in specific brain regions, and extracellular amyloid plaques, etc.
Presently there is no cure, for the disease, which worsens as it progresses, and eventually leads to death [3-6]. Currently, there are five medications that have approval for treatment of Alzheimer’s disease by the USA Food and Drug Administration (FDA. The majority of these approved pharmacotherapies are from a class of drugs known as acetycholinesterase (AChE) inhibitors and including tacrine, rivastigmine, galantamine and donepezil. These drugs do not cure Alzheimer’s disease, but can temporally ameliorate symptoms of cognition and memory. The other approved drug, memantine, is believed to help treat Alzheimer’s disease by interfering with or reducing the effects of a major excitatory protein found in the brain known as N-methyl D-aspartate (NMDA) receptor. Unfortunately, none of these drugs is curative, and, in fact, these pharmacotherapies have only modest positive therapeutic effects for the Alzheimer patient in regards to loss of memory. Moreover, the use of these drugs can also have unwanted side effects the limit the utility of the drugs. For example, a systematic review of a large number of evaluations of the efficacy and safety of memantine indicates that it does not improve cognition or learning/memory function among patients with mild cognitive impairment and it is associated with a greater risk of gastrointestinal harm. As of 2012, more than 1000 clinical trials have been completed or are underway for the treatment of Alzheimer’s disease; however, these trials have not yielded any significant advances in delaying the onset or slowing the progression of Alzheimer’s disease.
To this end, our laboratory has recently reported that dihydromyricetin (DHM), a plant flavonoid purified from Hovenia or teas that acts as a positive allosteric modulator of GABAA receptors (GABAARs; PTC Patent ID: 034044.089MX1, Liang 2011) can significantly improve cognitive/learning abilities as determined using a transgenic, mouse model of Alzheimer’s disease. Moreover, we showed that DHM could reverse the neuropathology of Alzheimer’s disease in this model. Mechanistically, we found that the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal slices from the transgenic mice of Alzheimer’s disease were significantly lower. We have named this phenomenon, the “silent inhibitory synapses”, because of the properties that we measured compared with control animals. We also found that gephyrin, a postsynaptic GABAAR anchor protein that regulates the formation and plasticity of GABAergic synapses, was reduced to less than 50% in hippocampus and cortex of Alzheimer’s diseased animals compared to that of control wild type animals. Interestingly, there were no significant differences in the GABAAR subunit levels of the Alzheimer’s disease versus control animals. Notably, we found that oral administration of DHM for 3 months restored gephyrin levels in a dose-dependent manner and restored GABAergic transmission as well as functional synapses in our transgenic, mouse model of Alzheimer’s disease. In addition, DHM treatment reduced amyloid-β (Ab) peptides in the brain of these animals. Importantly, the pathological recovery resulting from DHM treatment were parallel with improvement of cognition/learning ability and also showed a reduction of anxiety and seizure susceptibility in these transgenic animals. Collectively, the evidence supports the development of DHM as a novel pharmacotherapy for the treatment of Alzheimer’s disease.