Protein misfolding during bouts of heavy inflammation cause of permanent neurological issues afterward

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Int Rev Neurobiol. 2007;82:1-27.Click here to read Links

*Inflammatory mediators leading to protein misfolding and

uncompetitive/fast off-rate drug therapy for neurodegenerative disorders.*

Lipton SA, Gu Z, Nakamura T.

Neuroscience and Aging Center, Burnham Institute for Medical Research, La

Jolla, California 92037, USA.

*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 - indexed for MEDLINE]