" UFO drugs"

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

" UFO drugs"

Postby TwistedHelix » Tue Aug 07, 2007 11:24 am

This abstract ties together a number of common themes, and I particularly liked the idea that this reaction can resemble the effect of genetic mutations. Looks like the drugs are already being used for some diseases:

Inflammatory Mediators Leading to Protein Misfolding and Uncompetitive/Fast Off-Rate Drug Therapy for Neurodegenerative Disorders.
Int Rev Neurobiol. 2007;82C:1-27
Authors: Lipton SA, Gu Z, Nakamura T
Inflammatory mediators, including free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegenerative diseases in part by triggering protein misfolding. In this chapter, we will discuss a newly discovered pathway for this phenomenon and possible novel treatments. Excitotoxicity, defined as overstimulation of glutamate receptors, has been implicated in a final common pathway contributing to neuronal injury and death in a wide range of acute and chronic neurological disorders, ranging from Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Alzheimer's disease (AD) to stroke and trauma. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, leading to excessive Ca(2+) influx through the receptor's associated ion channel and subsequent free radical production, including NO and ROS. These free radicals can trigger a variety of injurious pathways, but newly discovered evidence suggests that some proteins are S-nitrosylated (transfer of NO to a critical thiol group), and this reaction can mimic the effect of rare genetic mutations. This posttranslational modification can contribute to protein misfolding, triggering neurodegenerative diseases. One such molecule affected is protein disulfide isomerase (PDI), an enzyme responsible for normal protein folding in the endoplasmic greticulum (ER). We found that when PDI is S-nitrosylation (forming SNO-PDI), the function of the enzyme is compromised, leading to misfolded proteins and contributing to neuronal cell injury and loss. Moreover, SNO-PDI occurs at pathological levels in several human diseases, including AD and PD. This discovery thus links protein misfolding to excitotoxicity and free radical formation in a number of neurodegenerative disorders. Another molecule whose S-nitrosylation can lead to abnormal protein accumulation is the E3 ubiquitin ligase, parkin, which contributes to the pathogenesis of PD. One way to ameliorate excessive NO production and hence abnormal S-nitrosylations would be to inhibit NMDA receptors. In fact, blockade of excessive NMDA receptor activity can in large measure protect neurons from this type of injury and death. However, inhibition of the NMDA receptor by high-affinity antagonists also blocks the receptor's normal function in synaptic transmission and leads to unacceptable side effects. For this reason, many NMDA receptor antagonists have disappointingly failed in advanced clinical trials. Our group was the first to demonstrate that gentle blockade of NMDA receptors by memantine, via a mechanism of uncompetitive open-channel block with a rapid "off-rate," can prevent this type of damage in a clinically efficacious manner without substantial side effects. For these Uncompetitive/Fast Off-rate therapeutics, we use the term "UFO drugs" because like Unidentified Flying Objects, they leave very quickly as soon as their job is finished. As a result, memantine blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this by preferentially entering the receptor-associated ion channel when it is excessively open, and, most importantly, when its off-rate from the channel is relatively fast so that it does not accumulate to interfere with normal synaptic transmission. Hence, memantine is clinically well tolerated, has been used in Europe for PD for many years, and recently passed multiple phase III trials for dementia, leading to its approval by the FDA and European Union for moderate-to-severe AD. Clinical studies of memantine for additional neurological disorders, including other dementias, neuropathic pain, and glaucoma, are underway. We have also developed a series of second-generation drugs that display greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, including critical thiol groups that are S-nitrosylated. In this case, in contrast to PDI or parkin, S-nitrosylation proves to be neuroprotective by decreasing excessive NMDA receptor activity. Targeted S-nitrosylation of the NMDA receptor can be achieved by coupling NO to memantine, yielding second-generation "UFO drugs" known as NitroMemantines.
PMID: 17678953 [PubMed - as supplied by publisher]
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UFO "Memantine"

Postby Shayk » Sun Aug 12, 2007 8:09 pm

Dom--

Thanks for that "tying it together" abstract. First it was the return of the astrocytes and now it's the UFOs...

Looks like the drugs are already being used for some diseases:

Inflammatory Mediators Leading to Protein Misfolding and Uncompetitive/Fast Off-Rate Drug Therapy for Neurodegenerative Disorders.
Int Rev Neurobiol. 2007;82C:1-27
Authors: Lipton SA, Gu Z, Nakamura T

The drug they mention, memantine, is in trial for cognitive disorders in people with MS. Hopefully we'll know sooner rather than later if it might be applicable to MS.

Interestingly, in EAE trials over 10 years ago, it didn't seem to do jack for inflammation but it prevented CNS injury.

Memantine abrogates neurological deficits, but not CNS inflammation

In mice it also seemed to impact the BBB.

And, this article posted by another member some time ago, notes
Stys and his team also found a drug already on the market to treat brain disease can block the pores of the myelin sheath.
I think the drug on the market that they referenced is memantine--so all in all, I think it's something to watch. The info you posted makes me want to watch it even more. Thanks!

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Re:

Postby CureOrBust » Sat Jun 15, 2013 5:24 am

Stumbled across this old thread and found the research results. Not good, so I thought I would just post the results to put some closure on it.

http://www.ncbi.nlm.nih.gov/pubmed/19092106
Memantine induces reversible neurologic impairment in patients with MS.
BACKGROUND:
Cognitive dysfunction is very common in multiple sclerosis (MS) and it severely impairs patients' quality of life. Thus, we explored whether memantine might improve cognitive performance in patients with MS.
METHODS:
We conducted a pilot trial with memantine (30 mg/day) in patients with MS with cognitive impairment. The trial was designed as a 1-year, randomized, double-blind, crossover study comparing memantine against a placebo in 60 patients with MS and cognitive impairment. Cognitive impairment was defined as the performance 1.5 standard deviations below the normative data in at least two tests of two cognitive domains in the Brief Repeatable Battery-Neuropsychology. The primary endpoint was improvement of verbal memory and the secondary endpoints were safety and improvements in the other cognitive domains, disability and quality of life. The trial was registered at http://www.clinicaltrials.org: NCT00638833.
RESULTS:
Although 19 patients had been included, the trial was halted after nine patients reported a worsening of their neurologic symptoms that deteriorated their quality of life. Seven of the nine patients in the memantine arm had blurred vision, fatigue, severe headache, increased muscle weakness, walking difficulties, or unstable gait. Only two patients in the placebo group reported neurologic symptoms and in both cases they were related with changes in their disease-modifying therapy. The adverse events only occurred on reaching the maximum dose (30 mg/day). After stopping medication, the patients reverted to their baseline disability within a few days.
CONCLUSIONS:
Memantine at a dose of 30 mg/day may induce transient worsening of neurologic symptoms of multiple sclerosis.
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