The Search for Neuroprotective Parkinson's Therapies

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Several anti-diabetes agents hold promise for Parkinson's disease-related neurodegeneration.

The Search for Neuroprotective Parkinson's Therapies
The Search for Neuroprotective Parkinson's Therapies

Treatments for Parkinson's disease are greatly limited by the fact that there is ongoing exploration into the disease's pathogenesis. Current treatments revolve around dopaminergic therapies, which although effective, can cause severe side effects after long-term use and do not slow down disease progression.

Therefore, it has become urgent to establish a neuroprotective or restorative therapy that addresses the underlying mechanism of the disease.1

“We want to find ways to slow or stop progression of the disease, so that it would be halted in the early stages when it's easy to treat, and before these other symptoms develop,” said David Simon, MD, PhD, of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston.

“The details of the pathogenesis of PD remain unclear, but the process undoubtedly involves mitochondrial dysfunction, abnormal handling of excessive levels or abnormal proteins by the cell, cell-to-cell spread of abnormal proteins, and neuroinflammation,” Thomas Foltynie, of Univeristy College of London Institute of Neurology in the United Kingdom told Neurology Advisor. “Despite the lack of complete understanding, it is clear that a therapy with beneficial effects on one or more of these mechanisms may result in neuroprotection.”

Does Insulin Resistance Hold the Key?

The associations between Parkinson's disease (PD) and other conditions, such as diabetes, are based on the current understandings of the mechanisms of insulin resistance caused by mitochondrial dysfunction.

PD patients have abnormal glucose tolerance, and concurrent diabetes in PD patients can accelerate motor and cognitive symptoms, study findings have indicated.

“Insulin resistance can be caused by mitochondrial dysfunction and vice versa. PD can be caused by mitochondrial dysfunction,” Foltynie said. “The most tantalizing observation is that insulin receptor stimulation in the brain leads to changes in expression of a protein called Akt, which has a direct influence on both mitochondrial dysfunction and neuronal survival, This is of major interest to investigators for PD as well as Alzheimer's disease and Huntington's disease.”

PPAR-y Agonists for Neurodegeneration in PD

Anti-diabetes agents, especially the peroxisome proliferator-activated receptor gamma (PPAR-y) agonist, pioglitazone, is being targeted as a potential.2 treatment of neurodegeneration in PD because of its effects on mitochondrial function.1,2

“By binding to the PPAR-gamma receptor, pioglitazone increases transcription of genes involved in insulin sensitivity and thus reduces insulin resistance,” Foltynie said. “Pioglitazone also binds to the outer mitochondrial membrane protein (MitoNEET), and there is some published evidence that it enhances mitochondrial function through an increase in complex 1 activity potentially relevant to both type 2 diabetes and PD.”

The neuroprotective effects of PPAR gamma are threefold, according to Marina Emborg, PhD, of the University of Wisconsin in Madison. They offer: monoamine oxidase inhibitor-B (MAO-B) inhibition, anti-inflammation, and decreased oxidative stress.

This was highlighted in a study published by Emborg and colleagues in the Journal of Neuroinflammation. In the study, the researchers demonstrated that pioglitazone modulates inflammation and induces neuroprotection in Parkinsonian monkeys.3

“The goal of the study was to assess if pioglitazone could prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like state in monkeys,” Emborg said. “We started pioglitazone administration 24 hours after a single intracarotid artery dose of MPTP in order to mimic ongoing neurodegeneration and minimize the confounding effect of MAO-B inhibition, [because] MPTP metabolism is basically completed eight hours after dosing. We found neuroprotection and most interestingly decreased neuroinflammation.”

 “[The] study confirmed that pioglitazone could protect against toxicity caused by MPTP. For MPTP to be toxic, it is metabolized by MAO-B to the active toxin MPP+. The concern was whether pioglitazone was protective simply by inhibiting MAO-B,” Foltynie added.

This concern was highlighted at the American Neurological Association's 2014 Annual Meeting, where researchers involved in the FS-Zone study presented a poster demonstrating that pioglitazone was not effective for treating PD.4

“The trial showed no benefit from pioglitazone, which is a major disappointment, and perhaps indicates that some of the encouraging lab data was simply related to the effects of pioglitazone on MAO-B, rather than having sufficient effects on mitochondria,”  Foltynie said. 

Going Forward

Despite the setback, Simon and colleagues are continuing to evaluate the upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) activity and the effects on inflammation and oxidative damage in an ongoing study.4,5

“We're testing levels of expression of PGC-1 alpha in white blood cells, levels of interleukin-6 (a marker of inflammation) in plasma, and levels of 8OHdG (a marker of oxidative damage) in urine,” Simon said.

“If pioglitazone induces the predicted changes in these biomarkers, then we can see if the changes in one or more of these biomarkers correlates with its protective effects. We can also test whether baseline levels of these biomarkers are predictive of the rate of progression of PD.”

Foltynie and colleagues are also evaluating another anti-diabetes agent, exenatide, in a phase II study as a potential neuroprotective treatment for PD.6 “The potential mechanism may relate to changes in expression level of Akt,” he said. The results of the trial should be available in the next 18 months.

Beth Gilbert is a freelance health and science writer. She has an undergraduate degree in chemical engineering from Lehigh University and a Master's in biomedical engineering from Columbia University.

References

  1. Carta AR, Simuni T. Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson's disease. Expert Opin Investig Drugs. 2014; 24 (3):1-9.
  2. Aviles-Olmos I, Limousin P et al. Parkinson's disease, insulin resistance and novel agents of neuroprotection. Brain. 2013; 136: 374-384.
  3. Swanson CR, Joers V et al. The PPAR-y agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys. Journal of Neuroinflammation. 2011;8(91):1-14.
  4. ClinicalTrials.gov. Pioglitazone in Early Parkinson's disease. Available at: http://clinicaltrials.gov/show/NCT01280123. Accessed: October 29, 2014.
  5. The Michael J. Fox Foundation for Parkinson's Research. “Biomarkers of Pioglitazone Effects in Parkinson's Disease (BioPEP).” Available at: https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=626. Accessed: October 29, 2014. 
  6. University College of London. Exenatide PD. Available at: www.ucl.ac.uk/exenatide-pd. Accessed: October 31, 2014.
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