Targeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases.

N-methyl-d-aspartate receptors (NMDARs) are the main class of ionotropic receptors for the excitatory neurotransmitter glutamate. They play a crucial role in the permeability of Ca2+ ions and excitatory neurotransmission in the brain. Being heteromeric receptors, they are composed of several subunits, including two obligatory GluN1 subunits (eight splice variants) and regulatory GluN2 (GluN2A~D) or GluN3 (GluN3A~B) subunits. Widely distributed in the brain, they regulate other neurotransmission systems and are therefore involved in essential functions such as synaptic transmission, learning and memory, plasticity, and excitotoxicity. The present review will detail the structure, composition, and localization of NMDARs, their role and regulation at the glutamatergic synapse, and their impact on cognitive processes and in neurodegenerative diseases (Alzheimer's, Huntington's, and Parkinson's disease). The pharmacology of different NMDAR antagonists and their therapeutic potentialities will be presented. In particular, a focus will be given on fluoroethylnormemantine (FENM), an investigational drug with very promising development as a neuroprotective agent in Alzheimer's disease, in complement to its reported efficacy as a tomography radiotracer for NMDARs and an anxiolytic drug in post-traumatic stress disorder.

Fluoroethylnormemantine (FENM) shows synergistic protection in combination with a sigma-1 receptor agonist in a mouse model of Alzheimer's disease.

Fluoroethylnormemantine (FENM) is a Memantine derivative with anti-amnesic and neuroprotective activities showed in the Aß25-35 pharmacological mouse model of Alzheimer's disease (AD). As AD is a complex multi-factorial neurodegenerative pathology, combination therapies relying on drugs acting through different pathways, have been suggested to more adequately address neuroprotection. As several agonists of the sigma-1 receptor (S1R), an intracellular chaperone, are presently in phase 2 or 3 clinical trials in neurodegenetrative diseases including AD, we examined the potentialities of S1R drug-based combinations with FENM, or Memantine. Aß25-35-treated mice were treated with S1R agonists (PRE-084, Igmesine, Cutamesine) and/or FENM, or Memantine, during 7 days after intracerebroventricular administration of oligomerized Aß25-35. Mice were then tested for spatial short-term memory on day 8 and non-spatial long-term memory on days 9-10, using the spontaneous alternation or passive avoidance tests, respectively. The FENM or Memantine combination with Donepezil, that non-selectively inhibits acetylcholinesterase and activates S1R, was also tested. The efficacy of combinations using maximal non-active or minimal active doses of S1R agonist or FENM was analyzed using calculations of the combination index, based on simple isobologram representation. Data showed that most of the FENM-based combinations led to synergistic protection against Aß25-35-induced learning deficits, for both long- and short-term memory responses, with a higher efficiency on the latter. Memantine led to synergistic combination in short-term memory but poorly in long-term memory responses, with either PRE-084 or Donepezil. These study showed that drug combinations based on FENM and S1R agonists may lead to highly effective and synergistic protection in AD, particularly on short-term memory.

Chronic intraperitoneal injection of polyethylene glycol 200 in mice induces hippocampal neuroinflammation.

In vivo treatment of hydrophobic substances requires the use of organic solvents, which are often toxic. Consequently, polyethylene glycols (PEGs), which are considered as nontoxic, have been widely used for many years in chemistry and biology. We used PEG 200, which was administrated by intraperitoneal (i.p.) injection once a week to mice. After 4 months of injections, at the dose of 1.67 mL/kg, a surprising increase in expression of GFAP (glial fibrillary acidic protein) and IBA1 (ionized calcium binding adaptor molecule 1), glial markers of astrocytes and microglia respectively, was observed in the mice's hippocampus. These results were associated with a dramatic increase in pro-inflammatory cytokine interleukin-1ß (IL-1ß) expression, all together suggesting an inflammatory process. It is important to communicate these results to the scientific community to provide awareness of this potential effect when PEG 200 is used under similar conditions as a vehicle in mice.

Monitoring of a progressive functional dopaminergic deficit in the A53T-AAV synuclein rats by combining 6-[18F]fluoro-L-m-tyrosine imaging and motor performances analysis.

With the emergence of disease-modifying therapies for Parkinson's disease, reliable longitudinal markers are needed to quantify pathology and demonstrate disease progression. We developed the A53T-AAV rat model of synucleinopathy by combining longitudinal measures over 12 weeks. We first characterized the progression of the motor and dopaminergic deficits. Then, we monitored the disease progression using the [18F]FMT Positron Emission Tomography (PET) radiotracer. The nigral injection of A53T-AAV led to an increase in phosphorylated α-synuclein on S129, a progressive accumulation of α-synuclein aggregates, and a decrease of dopaminergic function associated with a deterioration of motor activity. The longitudinal monitoring of A53T-AAV rats with [18F]FMT PET showed a progressive reduction of the Kc outcome parameter in the caudate putamen from the lesioned side. Interestingly, the progressive reduction in the [18F]FMT PET signal correlated with defects in the stepping test. In conclusion, we established a progressive rat model of α-synuclein pathology which monitors the deficit longitudinally using both the [18F]FMT PET tracer and behavioral parameters, 2 features that have strong relevance for translational approaches.

Trans ε-Viniferin Decreases Amyloid Deposits With Greater Efficiency Than Resveratrol in an Alzheimer's Mouse Model.

In a previous study, we showed that viniferin decreased amyloid deposits and reduced neuroinflammation in APPswePS1dE9 transgenic mice between 3 and 6 months of age. In the present study, wild type and APPswePS1dE9 transgenic mice were treated from 7 to 11 or from 3 to 12 months by a weekly intraperitoneal injection of either 20 mg/kg viniferin or resveratrol or their vehicle, the polyethylene glycol 200 (PEG 200). The cognitive status of the mice was evaluated by the Morris water maze test. Then, amyloid burden and neuroinflammation were quantified by western-blot, Enzyme-Linked ImmunoSorbent Assay (ELISA), immunofluorescence, and in vivo micro-Positon Emission Tomography (PET) imaging. Viniferin decreased hippocampal amyloid load and deposits with greater efficiency than resveratrol, and both treatments partially prevented the cognitive decline. Furthermore, a significant decrease in brain uptake of the TSPO PET tracer [18F]DPA-714 was observed with viniferin compared to resveratrol. Expression of GFAP, IBA1, and IL-1ß were decreased by viniferin but PEG 200, which was very recently shown to be a neuroinflammatory inducer, masked the neuroprotective power of viniferin.

Natural stilbenes effects in animal models of Alzheimer's disease.

Alzheimer's disease is one of the most frequent neurodegenerative diseases. This pathology is characterized by protein aggregates, mainly constituted by amyloid peptide and tau, leading to neuronal death and cognitive impairments. Drugs currently proposed to treat this pathology do not prevent neurodegenerative processes and are mainly symptomatic therapies. However, stilbenes presenting multiple pharmacological effects could be good potential therapeutic candidates. The aim of this review is to gather the more significant papers among the broad literature on this topic, concerning the beneficial effects of stilbenes (resveratrol derivatives) in animal models of Alzheimer's disease. Indeed, numerous studies focus on cellular models, but an in vivo approach remains of primary importance since in animals (mice or rats, generally), bioavailability and metabolism are taken into account, which is not the case in in vitro studies. Furthermore, examination of memory ability is feasible in animal models, which strengthens the relevance of a compound with a view to future therapy in humans. This paper is addressed to any researcher who needs to study untested natural stilbenes or who wants to experiment the most effective natural stilbenes in largest animals or in humans. This review shows that resveratrol, the reference polyphenol, is largely studied and seems to have interesting properties on amyloid plaques, and cognitive impairment. However, some resveratrol derivatives such as gnetin C, trans-piceid, or astringin have never been tested on animals. Furthermore, pterostilbene is of particular interest, by its improvement of cognitive disorders and its neuroprotective role. It could be relevant to evaluate this molecule in clinical trials.

Natural polyphenols effects on protein aggregates in Alzheimer's and Parkinson's prion-like diseases.

Alzheimer's and Parkinson's diseases are the most common neurodegenerative diseases. They are characterized by protein aggregates and so can be considered as prion-like disease. The major components of these deposits are amyloid peptide and tau for Alzheimer's disease, α-synuclein and synphilin-1 for Parkinson's disease. Drugs currently proposed to treat these pathologies do not prevent neurodegenerative processes and are mainly symptomatic therapies. Molecules inducing inhibition of aggregation or disaggregation of these proteins could have beneficial effects, especially if they have other beneficial effects for these diseases. Thus, several natural polyphenols, which have antioxidative, anti-inflammatory and neuroprotective properties, have been largely studied, for their effects on protein aggregates found in these diseases, notably in vitro. In this article, we propose to review the significant papers concerning the role of polyphenols on aggregation and disaggregation of amyloid peptide, tau, α-synuclein, synphilin-1, suggesting that these compounds could be useful in the treatments in Alzheimer's and Parkinson's diseases.