MS and Parkinson's disease (PD) share a common underlying disease pathway. For instance, patients with PD also have elevated levels of TNF, IL-6, and interferon-gamma. I thought the following study on the association of interferon-gamma with PD and the loss of dopaminergic neurons was especially interesting.
J Neurosci. 2007 Mar 21;27(12):3328-37.Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons.
Mount MP, Lira A, Grimes D, Smith PD, Faucher S, Slack R, Anisman H, Hayley S, Park DS.
"Growing evidence implicates microglia in the loss of dopaminergic neurons in Parkinson's disease (PD). However, factors mediating microglial activation in PD are poorly understood. Proinflammatory cytokines, such as interferon-gamma (IFN-gamma), orchestrate the actions of microglia. We report here that PD patients express significantly elevated levels of IFN-gamma in their blood plasma...Together, these data suggest that IFN-gamma participates in death of dopaminergic neurons by regulating microglial activity.http://www.ncbi.nlm.nih.gov/pubmed/17376993
TNF has also been implicated in PD and the death of dopaminergic neurons, as the following study confirms.
Exp Neurol. 2001 Jun;169(2):219-30.
Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons.
McGuire SO, Ling ZD, Lipton JW, Sortwell CE, Collier TJ, Carvey PM."Levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) are increased in postmortem brain and cerebral spinal fluid from patients with Parkinson's disease (PD). This observation provides a basis for associating TNFalpha with neurodegeneration...These data strongly suggest that TNFalpha mediates cell death in a sensitive population of DA neurons and support the potential involvement of proinflammatory cytokines in the degeneration of DA neurons in PD."http://www.ncbi.nlm.nih.gov/pubmed/11358437
INTERFERON-GAMMA AND INCREASED KYNURENINE PATHWAY ACTIVITY
The "kynurenine pathway" is a tryptophan degrading pathway. The body has alternate pathways to metabolize the essential amino acid tryptophan. In one pathway, tryptophan is metabolized through the serotonin pathway. In another, called the kynurenine pathway, tryptophan is used to make niacin (B3). The majority of dietary tryptophan (95%) is oxidized through the kynurenine pathway, and just a small portion is used for the synthesis of serotonin.
Indoleamine 2,3 dioxygenase (IDO) is one of the enzymes that degrades tryptophan in the kynurenine pathway. Tryptophan degradation by IDO is normally very moderate, but if the cytokines interferon-gamma and tumor necrosis factor are elevated, IDO can be upregulated. The upregulation of IDO by interferon-gamma and tumor necrosis factor depletes tryptophan and creates an excess of toxic metabolites such as kynurenic acid, kynurenine, and quinolinic acid.
In the following study the researchers concluded that interferon-gamma, “in particular”, induced the enzyme IDO.
FASEB J. 1991 Aug;5(11):2516-22.
Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism.
Taylor MW, Feng GS
“…In particular, interferon-gamma (IFN-gamma) induces an enzyme of tryptophan catabolism, indoleamine 2,3-dioxygenase (IDO), which is responsible for conversion of tryptophan and other indole derivatives to kynurenine…”
The following study confirms that kynurenine pathway activity is involved in MS. The researchers found elevated levels of the toxic tryptophan metabolite “kynurenic acid” in patients with MS and concluded their data demonstrated the involvement of the kynurenine system in the pathogenesis of MS.
Acta Neurol Scand. 2005 Aug;112(2):93-6.
Kynurenine metabolism in multiple sclerosis.
Hartai Z, Klivenyi P, Janaky T, Penke B, Dux L, Vecsei L.
“…The concentration of kynurenic acid is elevated in the plasma of MS patients, and there is a tendency to an elevation in the RBC…Our data demonstrate the involvement of the kynurenine system in the pathogenesis of MS…”
Researchers in the following study stated that evidence has progressively emerged suggesting that the kynurenine pathway (KP) is involved in the pathogenesis of autoimmune diseases, especially MS.
We would also expect to find the kynurenine pathway involved in Parkinson's disease, due to the elevated levels of interferon-gamma and TNF. As the following study states, "The KP is known to be involved in several neuroinflammatory disorders including...Parkinson's disease."
Int J Tryptophan Res. 2010; 3: 157–167.
Understanding the roles of the kynurenine pathway in multiple sclerosis progression.
Chai K. Lim,1 Bruce J. Brew,2,3 Gayathri Sundaram,1 and Gilles J. Guillemin1
“…The KP is known to be involved in several neuroinflammatory disorders including Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia complex, Parkinson's disease,
schizophrenia, Huntington's disease and brain tumours…Over the last 2–3 years, some evidence has progressively emerged suggesting that the KP is likely to be involved in the pathogenesis of autoimmune diseases especially MS.
Some KP modulators are already in clinical trials for other inflammatory diseases and would potentially provide a new and important therapeutic strategy for MS patients…”
In the following study researchers discovered that the kynurenine pathway neurotoxin “quinolinic acid” was selectively elevated in experimental allergic encephalomyelitis, the animal model of MS.
J Neurochem. 1995 Mar;64(3):1192-6.
Neurotoxin quinolinic acid is selectively elevated in spinal cords of rats with experimental allergic encephalomyelitis.
Flanagan EM, Erickson JB, Viveros OH, Chang SY, Reinhard JF Jr
“Experimental allergic encephalomyelitis (EAE) is an autoimmune, animal model of multiple sclerosis (MS) in which demyelination and paralysis are evident. Quinolinic acid (QUIN) is a neurotoxin…formed from tryptophan
…Lewis rats inoculated with myelin basic protein developed signs of EAE by day 12, were killed, and their tissues assayed for QUIN by gas chromatography with mass spectrometry. QUIN levels were significantly elevated in the more caudal regions of the spinal cords of animals with EAE
The toxic metabolites produced through increased kynurenine pathway activity--kynurenic acid, kynurenine, and quinolinic acid--have been demonstrated to be involved in oligodendrocyte loss, depression, bipolar disorder, seizures, low GABA, elevated glutamate, sensorineural hearing loss, suicide, interstitial cystitis, and irritable bowel syndrome.
In the following study the researchers concluded their data indicated up to 54% reductions
in the number of oligodendrocytes after exposure to quinolinic acid.
Brain Res. 2001 Mar 30;896(1-2):157-60.
Oligodendrocyte killing by quinolinic acid in vitro.
Cammer W.“Quinolinic acid…can kill neurons in vivo and in vitro
. To test whether quinolinic acid is toxic to oligodendrocytes, glial cells cultured from the brains of 2-day-old rats were incubated with quinolinic acid at concentrations known to kill neurons. The cells were then fixed and immunostained with MAbO4 to mark immature and mature oligodendrocytes and anti-myelin basic protein (MBP) to mark mature oligodendrocytes. The data indicated up to 54% reductions in the numbers of O4-positive cells in cultures after incubation with quinolinic acid.
Apoptosis of O4-positive cells began during the first 6 h, and some of the apoptotic cells became fragmented. Further apoptosis, and clumping of dead MBP-positive oligodendrocytes, occurred during longer incubation with quinolinic acid…”