Inflammation
 

1: Trends Immunol. 2008 Aug;29(8):357-65. Epub 2008 Jul 1.

Why neurodegenerative diseases are progressive: uncontrolled inflammation drives
disease progression.

Gao HM, Hong JS.

Neuropharmacology Section, Laboratory of Pharmacology, National Institute of
Environmental Health Sciences/National Institutes of Health, Research Triangle
Park, NC 27709, USA. Gao2@niehs.nih.gov

Neurodegenerative diseases are a group of chronic, progressive disorders
characterized by the gradual loss of neurons in discrete areas of the central
nervous system (CNS). The mechanism(s) underlying their progressive nature
remains unknown but a timely and well-controlled inflammatory reaction is
essential for the integrity and proper function of the CNS. Substantial evidence
has documented a common inflammatory mechanism in various neurodegenerative
diseases. We hypothesize that in the diseased CNS, interactions between damaged
neurons and dysregulated, overactivated microglia create a vicious
self-propagating cycle causing uncontrolled, prolonged inflammation that drives
the chronic progression of neurodegenerative diseases. We further propose that
dynamic modulation of this inflammatory reaction by interrupting the vicious
cycle might become a disease-modifying therapeutic strategy for neurodegenerative
diseases.


PMID: 18599350 [PubMed - indexed for MEDLINE]

Femtomolar Dextromethorphan! (Three years ago)
 

Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage
Li, G., Cui, G., Tzeng, N.-S., Wei, S.-J., Wang, T., Block M. I., Hong, J.-S.
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry and the National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
FASEB J. 19, 489-496 (2005)

Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease (PD). Progress in the search for effective therapeutic strategies that can halt this degenerative process remains limited. We previously showed that micromolar concentrations of dextromethorphan (DM) a major ingredient of widely used antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through the inhibition of microglial activation. In this study, we report that femto- and micromolar concentrations of DM (both pre- and post-treatment) showed equal efficacy in protecting lipopolysaccharide (LPS)-incuced dopaminergic neuron death in midbrain neuron-glia cultures. Both concentrations of DM decreased LPS-induced release of nitric oxide, tumor necrosis factor-alpha, prostaglandin E2 and superoxide from microglia in comparable degrees. The important role of superoxide was demonstrated by DM's failure to show a neuroprotective effect in neuron-glia cultures from NADPH oxidase-deficient mice. These results suggest that the neuroprotective effect elicited by femtomolar concentrations of DM is mediated through the inhibition of LPS-induced proinflammatory factors, especially superoxide. These finding suggest a novel therapeutic concept of using "ultra-low" drug concentrations for the intervention of inflammation-related neurodegenative diseases.

doi: 10. 1096/fj.04-2555com

I realize that LDN and LDDM are not a cure for PD, and some people like Rick may have some problems taking it, but there are several of us that have achieved what we think are significant benefits in the direction of slowing progression. I do not hesitate to urge my own family members who may be at risk for developing PD to take low-dose dextromethorphan. To me, it is a no-brainer for non-symptomataic but susceptible people, or for someone who is very early in the disease process.

Robert

LDN and neuroinflammation
 

Hello,
Like Robert, I have been taking a drug similar to DM. It is 4.5 mg of naltrexone or Low Dose Naltrexone. I have been taking LDN along with 600 mg of Q10 for the past 54 months in addition to my rather low doses of Sinemet and Mirapex. I don't think I've progressed over that time and I have not had to increase my PD meds.
The NIH has done some research on opioid type drugs at low doses which seem to mitigate neuroinflammation. See below.
Ashley

http://www.ncbi.nlm.nih.gov/pubmed/1...?dopt=Abstract

Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.

Inflammation has been increasingly recognized to contribute to the pathogenesis of Parkinson's disease. Several compounds are neuroprotective at femtomolar concentrations through the inhibition of inflammation. However, the mechanisms mediating femtomolar-acting compounds are poorly understood. Here we show that both gly-gly-phe (GGF), a tri-peptide contained in the dynorphin opioid peptide, and naloxone are neuroprotective at femtomolar concentrations against LPS-induced dopaminergic neurotoxicity through the reduction of microglial activation. Mechanistic studies demonstrated the critical role of NADPH oxidase in the GGF and naloxone inhibition of microglial activation and associated DA neurotoxicity. Pharmacophore analysis of the neuroprotective dynorphin peptides and naloxone revealed common chemical properties (hydrogen bond acceptor, hydrogen bond donor, positive ionizable, hydrophobic) of these femtomolar-acting compounds. These results support a common high-affinity site of action for several femtomolar-acting compounds, where NADPH oxidase is the critical mechanism governing neuroprotection, suggesting a novel avenue of anti-inflammatory and neuroprotective therapy.

Curcumin is our oldest experiment
 

Ron's been using it for years and you just can't stop the fellow.:) The only caveat I can think of is if you have h pylori grt rid of it first or take a hardened tablet that will get past the stomach before disinterating. Curcumin kills HP better than any antibiotic. Also, maximum bio-availability comes from taking it with a little oil of some sort.

1: Int J Biochem Cell Biol. 2008 Jul 9. [Epub ahead of print]

Potential therapeutic effects of curcumin, the anti-inflammatory agent, against
neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and
neoplastic diseases.

Aggarwal BB, Harikumar KB.

Cytokine Research Laboratory, Department of Experimental Therapeutics, The
University of Texas M. D. Anderson Cancer Center, Houston, TX, United States.

Although safe in most cases, ancient treatments are ignored because neither their
active component nor their molecular targets are well defined. This is not the
case, however, with curcumin, a yellow-pigment substance and component of
turmeric (Curcuma longa), which was identified more than a century ago. For
centuries it has been known that turmeric exhibits anti-inflammatory activity,
but extensive research performed within the past two decades has shown that this
activity of turmeric is due to curcumin (diferuloylmethane). This agent has been
shown to regulate numerous transcription factors, cytokines, protein kinases,
adhesion molecules, redox status and enzymes that have been linked to
inflammation. The process of inflammation has been shown to play a major role in
most chronic illnesses, including neurodegenerative, cardiovascular, pulmonary,
metabolic, autoimmune and neoplastic diseases. In the current review, we provide
evidence for the potential role of curcumin in the prevention and treatment of
various proinflammatory chronic diseases. These features, combined with the
pharmacological safety and negligible cost, render curcumin an attractive agent
to explore further.