Protein Inhibitor Tangles With Alzheimer's Disease

ScienceDaily (Feb. 15, 2007) — Mayo Clinic researchers have now shown that a drug that inhibits the function of the protein Hsp90 reduces brain levels in mice of the protein tau, the abnormal accumulation of which has been implicated in the pathogenesis of Alzheimer's disease (AD).

A hallmark of AD is the abnormal accumulation of phosphorylated tau (p-tau) proteins resulting in the formation of neurofibrillary tangles, which impair the function of brain axons. Enhancing the removal of these p-tau proteins may therefore be a relevant therapeutic strategy.

In the current study, Leonard Petrucelli and colleagues from the Mayo Clinic showed that a complex of two proteins, CHIP and Hsp90 (which are involved in protein refolding and degradation), plays a role in alleviating p-tau accumulation in mice and cultured human cells. They went on to show that administration of an Hsp90 inhibitor, EC102, to mice overexpressing human tau caused a significant reduction in p-tau levels.

The findings point to a pivotal role for Hsp90 in aberrant tau degradation and potentially in tau refolding. Unlike many drugs, EC102 is able to cross the blood-brain barrier, making it a highly promising therapeutic candidate for AD and other conditions in which tau accumulates in abnormally high levels in the brain.

http://www.sciencedaily.com/releases/2007/02/070215181509.htm

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

Abstract
K252a and staurosporine microbial alkaloid toxins as prototype of neurotropic drugs.

K252 family of alkaloid toxins-kinase inhibitors are the most widely used compounds in biological research on the role of protein kinases in cellular transduction systems, biological functions and pathophysiology of neurological disorders.

The wide research interest in these toxins is due to their potency in inhibiting cellular protein kinases. However, lack of kinase specificity is one of their major drawbacks. Synthesis of new K252 derivatives can be expected to open up a new generation of kinase inhibitors.

Staurosporine might be considered as a prototype neurotropic drug in view of its ability to induce neurite outgrowth and to increase tau protein levels. Because it mimics some of the neuroprotective effects of NGF and might blocks certain signals required to enhance cellular levels and/or beta amyloid processing, staurosporine might play a beneficial role in the treatment of Alzheimer's disease.

The ability of staurosporine to promote neuronal regeneration and brain cholinergic neurons survival has been also demonstrated in animal studies (Nabeshima et al., 1991).

The beneficial effects of K252a on the experimental autoimmune encephalomyelitis (EAE) disease mice model and it's ability to supress macrophage activation suggest an important role of protein kinases inhibitors as immunosupressive agents.

These results may also point to the potential clinical relevance of K252 microbial toxins as prototypes for the development of new drugs for the management of neuronal diseases.

http://www.mendeley.com/research/k252a-staurosporine-microbial-alkaloid-toxins-prototype-neurotropic-drugs-1/

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

Interesting?

Neurotrophic Activities of K252a

Unexpectedly, K252a not only inhibits the effects of the neurotrophins but also
possesses “neurotrophic” activities. In embryonic chicken neurons in vitro, K252a
increases the survival of dorsal root ganglion (DRG) and ciliary ganglion neurons
in a dose-dependent manner; at the maximal dose tested, K252a maintains similar
numbers of DRG and ciliary ganglion neurons as maintained by NGF and ciliary
neurotrophic factor, respectively (68). This survival effect persists for at least two
weeks in these culture settings. K252a not only promotes survival but also induces
morphological changes, such as inducing neurite outgrowth, similar to a growth
factor (68).


The Synthesis of Semisynthetic K252a-Analogues that Increase ChAT Activity in Basal Forebrain and Spinal Cord Cultures

K252a possesses two activities in neurons. At high concentrations, K252a inhibits
the survival-promoting and neurotrophic effects of neurotrophins, whereas at low
concentrations, K252a, by itself, promotes survival and differentiation similar to
the effects of the neurotrophins.

http://p973.ccmu.edu.cn/4-zuixinjinzhan/2/26.pdf

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

Tau protein hyperphosphorylation in sporadic ALS with cognitive impairment

Abstract

The authors have characterized frontal cortical tau protein in cognitively intact (4) and cognitively impaired (ALSci, 4) ALS patients and compared it with control (2) or Alzheimer disease (AD, 1)- derived tau. The authors observed expression of both 3R and 4R tau isoforms; increased insoluble tau protein; phosphatase resistance; and hyperphosphorylation at T175, S208, and S210. Soluble tau from both AD and ALSci was also phosphorylated at S237. Tau hyperphosphorylation is associated with ALS.

http://www.neurology.org/content/66/11/1770.abstract

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which results from selective loss of upper and lower motor neurons. Mouse models of ALS, such as one carrying the G93A mutant of the human Cu-Zn superoxide dismutase gene[SOD1(G93A)], develop motor neuron pathology and clinical symptoms similar to those observed in ALS patients. There is compelling evidence that both direct and indirect glutamate toxicity contribute to the pathogenesis of motor neuron degeneration.

However, the therapeutic effect of various glutamate receptor antagonists has not been clearly demonstrated.

Memantine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. It has been shown to protect neurons against NMDA- or glutamate-induced toxicity in vitro and in animal models of neurodegenerative diseases.

In the current study, we have examined the therapeutic efficacy of memantine in an ALS mouse model carrying a high copy number of SOD1(G93A). Memantine treatment significantly delayed the disease progression and increased the life span of SOD1(G93A) mice, from 121.4 ± 5.5 to 129.7 ± 4.5 days (P = 0.032). Furthermore, NMDA receptor subunits were reliably detected in the spinal cord of SOD1(G93A) mice and their expression levels were similar to those in the wild-type littermate control. Therefore, the neuroprotective effect of memantine in SOD1(G93A) mice is most probably due to the inhibition of spinal cord NMDA receptors. In view of the long-term usage of memantine for dementia patients, with excellent tolerance and safety, these data suggest that memantine may be used in ALS patients alone or in combination with other therapies to prolong survival


http://www.ncbi.nlm.nih.gov/pubmed/20565333



A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis.

2010 Oct;11(5):456-60.

Source

Neuroscience Department, Hospital de Santa Maria-Centro Hospitalar Lisboa Norte, Lisbon, Portugal. mamedemg@mail.telepac.pt


Abstract

Our objective is to describe the results of a phase II/III, 12-months, double-blinded, single-centre, randomized, parallel (1:1), clinical trial performed to evaluate the efficacy and safety of memantine in ALS. Patients with probable or definite ALS of less than 36 months disease duration and progression over a one-month lead-in period were randomly assigned to placebo or memantine at 20 mg/day. The primary endpoint was 12-months ALSFRS decline. Forced vital capacity, manual muscle testing, visual analogue scale, quality of life, motor unit number estimation and neurophysiological index were the secondary endpoints. The number of patients included was based on the assumption of a 50% change in the ALSFRS decline. Safety and adverse events were evaluated. Sixty-three patients were included in the trial. Memantine did not show more adverse events or laboratory changes than placebo.

Primary and secondary outcomes were not different between groups by intention-to-treat and per-protocol analysis. The most sensitive measurements were neurophysiological, which declined linearly over time.
In conclusion, the results of this study show that memantine is well tolerated and safe in ALS patients. We did not observe any evidence of efficacy for memantine but we cannot exclude a positive outcome on survival

http://www.ncbi.nlm.nih.gov/pubmed/20565333


Maybe in requires a different dose or in conjunction with other drugs before it can be shown to help?

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again

Evaluation of drugs for treatment of prion infections of the central nervous system

Abstract

Prion diseases are fatal and at present there are neither cures nor therapies available to delay disease onset or progression in humans.

Inspired in part by therapeutic approaches in the fields of Alzheimer's disease and amyotrophic lateral sclerosis, we tested five different drugs, which are known to efficiently pass through the blood–brain barrier, in a murine prion model.

Groups of intracerebrally prion-challenged mice were treated with the drugs curcumin, dapsone, ibuprofen, memantine and minocycline.

Treatment with antibiotics dapsone and minocycline had no therapeutic benefit. Ibuprofen-treated mice showed severe adverse effects, which prevented assessment of therapeutic efficacy.

Mice treated with low- but not high-dose curcumin and mice treated with memantine survived infections significantly longer than untreated controls (P<0.01). These results encourage further research efforts to improve the therapeutic effect of these drugs

http://www.ncbi.nlm.nih.gov/pubmed/20839903

Notice how Ibuprofen-treated mice showed severe adverse effects but low dose curcumin and memantine survived longer?

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Into the heart, an air that kills, from yon far country blows.
What are those blue remembered hills, what sphires what farms are those.
That is the land of lost content,I see it shining plain,
The happy highways where I went and cannot come again