Fiercebiotechresearch reports
Quote:
Researchers at Sanford-Burnham Medical Research Institute in La Jolla, CA, have developed what they say is the first experimental drug meant to restore the synapses--or brain connections--destroyed in Alzheimer's disease.
In animal models as well as brain cells derived from human stem cells, scientists mapped the pathway that caused synaptic damage in Alzheimer's. They found that amyloid beta peptides--once thought to be the direct cause of synapse death--prompted the release of dangerously high amounts of the neurotransmitter glutamate, which promotes memory and learning at normal levels, from brain cells called astrocytes that are located next to the nerve cells. In Alzheimer's patients, excessive glutamate activates extrasynaptic receptors--also known as eNMDA receptors--get hyperactivated and cause synaptic loss.
To reverse this loss of synapses, investigators combined two FDA-approved medicines, nitroglycerin and memantine, to create a drug with a dual function. Memantine works by selectively binding to eNMDA receptors and targets nitroglycerin to the receptor. The drug essentially shuts down hyperactive eNMDA receptors on diseased neurons, restoring the synapses between those neurons and halting destructive brain changes that cause memory loss and cognitive decline.
The breakthrough article by Lipton et al. titled “Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss” Lipton et al. has been posted for early view in PNAS.
Quote:
Abstract
Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here we show that amyloid-β peptide (Aβ) engages α7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons.
Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from Aβ-induced damage both in vitro and in vivo.
As I understand now, synaptic and extrasynaptic NMDARs are different animals. One can apply agonists of synaptic NMDARs and antagonists of extrasynaptic NMDARs simultaneously.
See also previous report:
Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Lipton et al. Nat Med. 2009 December; 15(12): 1407–1413
Quote: Treatment of transgenic YAC128 HD mice with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine also blocks synaptic NMDAR activity, decreases neuronal inclusions, and worsens these outcomes.
Also:
Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways
Hardingham, Fukunaga, Bading Nature Neuroscience 5, 405 - 414 (2002)
Quote:
Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) receptors have opposite effects on CREB (cAMP response element binding protein) function, gene regulation and neuron survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have anti-apoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death. Specific blockade of extrasynaptic NMDA receptors may effectively prevent neuron loss following stroke and other neuropathological conditions associated with glutamate toxicity.
Now back to NitroMemantine.
There is a patent: Methods for treating neuropsychiatric disorders with NMDA receptors antagonists (EP 1852113 A2) filed in 2001.
Quote Abstract:
The Present invention relates to compositions and methods for treating a human patient afflicted with a neuropsychiatric disorder. Specifically, the invention provides for compositions and methods of modulating or antagonizing the activity of neuronal NMDA receptors, wherein such antagonistic activity is capable of modulating the glutamate induced excitatory response of the neurons, thereby inhibiting an excitotoxic effect, promoting a neurotrophic effect, and thereby providing a therapeutic effect that treats the neuropsychiatric disorder.
It specifically mentions NitroMemantine but does not claim it as a substance but rather that it can be used for treating neuropsychiatric disorders, such as major depression, bipolar disorder, anxiety, drug addiction.
It looks like one can synthetize it and legally use for personal “research” experimentation. At least until any clinical trials start.
What do you think people?
