Progress and Prospects in Parkinson's Research/Therapy/Neuroprotection/Isradipine

The initial hypothesis, which argues the case for Calcium Channel Blockers as a neuroprotective PD therapy, is sound and has the added attraction of using products already licenced for human use. However although preliminary research on mice produced promising results, subsequent research has had inconsistent outcomes.


BackgroundEdit

Isradipine is a Calcium Channel Blocker (CCB). Its trade names are DynaCirc and Prescal. It is prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack.

2007

Surmeier [1] puts foward the case for PD therapies based upon Calcium Channel Blockers.

A potential clue to the vulnerability of nigral neurons is their increasing reliance on Ca(2+) channels to maintain autonomous activity with age. This reliance could pose a sustained metabolic stress on mitochondria, accelerating cellular ageing and death. The Ca(2+) channels underlying autonomous activity in dopaminergic neurons are closely related to the L-type channels found in the heart and smooth muscle. Systemic administration of isradipine, a dihydropyridine blocker of L-type channels, forces dopaminergic neurons in rodents to revert to a juvenile, Ca(2+)-independent mechanism to generate autonomous activity. More importantly, reversion confers protection against toxins that produce experimental parkinsonism, pointing to a potential neuroprotective strategy for Parkinson's disease with a drug class that has been used safely in human beings for decades. These studies also suggest that, although genetic and environmental factors can hasten its onset, Parkinson's disease stems from a distinctive neuronal design common to all human beings, making its appearance simply a matter of time.

ResearchEdit

2010

Simon et al [2] conducted an epidemiological study of the effect of using a calcium channel blocker (CCB) on the onset of PD.

Their cohort was 121,700 females aged 30-55 and 51,529 males aged 40-75. There were 514 identified cases of PD and a 16 year follow-up. Their conclusion:-

These findings do not support a role for CCBs in providing neuroprotection against development of PD.


Simuni et al [3] tested the effects of giving 31 early stage PD patients graduated doses of isradipine for 8 weeks. It produced no measurable effect on their PD symptoms.

Ritz et al [4] worked with a cohort of 1,931 patients with a first time diagnosis for PD between 2001 and 2006.

Theyfound that subjects prescribed centrally acting calcium channel blockers (excludes amlodipine) between 1995 and two years prior to the index date were 27% less likely to develop Parkinson’s disease.

2011

Bagatini et al[5] induced Parkinsonism in fruit flies, using paraquat and the tested the effect of Calcium Channel Blockers.

The drugs tested were the dihydropyridines, isradipine, nifedipine, and nimodipine, and resveratrol, a polyphenol that presents antioxidant properties. Their conclusion:-

This study is the first demonstration that dyhidropyridines and resveratrol are unable to reverse the locomotor impairments induced by paraquat in Drosophila melanogaster.


Ilijic et al [6] tested isradipine on mice with MPTP-induced Parkinsonism.

This analysis revealed that isradipine produced a dose-dependent sparing of DA fibers and cell bodies at concentrations achievable in humans, suggesting that isradipine is a potentially viable neuroprotective agent for PD.

Rees et al [7] reviewed the arguments in favour of the use of anti-hypersensitive drugs such as Calcium Channel blockers in the treatment of diseases such as PD. Their conclusion:-

There is currently a lack of evidence for the use of antihypertensive drugs for either the primary or secondary prevention of PD. More observational studies are required to identify potential drugs to go forward for safety and tolerability studies in people with early PD

Further ReadingEdit

2009

Bezprozvanny, Ilya Full Text Trends Mol. Med. 15 (3) 89-100:

Calcium signaling and neurodegenerative diseases

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226745/?tool=pmcentrez


Guzman, Jaime N.; Sánchez-Padilla, Javier; Chan, C, Savio and Surmeier, D. James: Full Text J. Neurosci. 29 (35) 11011 -11019

Robust Pacemaking in Substantia Nigra Dopaminergic Neurons

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784968/?tool=pmcentrez


2011

Anekonda, Thimmappa S.; Quinn, Joseph F,; Harris, Christopher; Frahler, Kate; Wadsworth, Teri L.and Woltjer, Randall L. Full Text Neurobiol. Disord. 41 (1) 62-710

L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer’s disease

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982927/?tool=pmcentrez

Today

Use the following links to query the PubMed, PubMed Central and Google Scholar databases using the Search terms:- Parkinson's_Disease Isradipine.

This will list the latest papers on this topic. You are invited to update this page to reflect such recent results, pointing out their significance.

Pubmed (abstracts)

Pubmed_Central (Full_Text)

Google_Scholar

Related pagesEdit

Therapy > Neuroprotection

Sub Pages:

Neuroprotective agents
Substances with possible neuroprotective properties:
Caffeine,--Celastrol,--Co-Enzyme Q10,--Creatine,--DHA,--Exendin-4 (EX-4),--GDNF,--Glutathione (GSH),--GM1,--Isradipine,--Melatonin,--Minocycline,--Nicotine,--NSAIDs,--Phenylbutyrate,--Phytic Acid,--Probucol,--Quinoxaline,--Rasagiline,--Riboflavin,--Statins,--Tolcapone,--Urate & Uric Acid,--Vitamin D,--Vitamin E,--

ReferencesEdit

<references>

  1. Surmeier, D.J. Abstract (2007) Abstract Lancet Neurol. 6 (10) 933 – 938 Calcium, ageing, and neuronal vulnerability in Parkinson's disease. http://www.ncbi.nlm.nih.gov/pubmed/17884683
  2. Simon, K. Claire; Gao,Xiang; Chen, Honglei; Schwarzchild, Michael A. and Ascherio, Alberto (2010 )Full Text Mov. Disord. 25 (12) 1818 – 1822: Calcium channel blocker use and risk of Parkinson’s disease. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939261/?tool=pmcentrez
  3. Simuni T.; Borushko, E.; Avram, M. J.; Miskevics, S.; Martel, A.; Zadikoff, C.; Videnovic, A.; Weaver, F. M.; Williams, K. and Surmeier, D. J. (2010)Abstract Mov. Disord. 25 (16):2863 - 2866. Tolerability of isradipine in early Parkinson's disease: a pilot dose escalation study. http://www.ncbi.nlm.nih.gov/pubmed/20818667
  4. Ritz, Beate; Rhodes, Shannon L.; Lei Qian, Lei; Schernhammer, Eva; Olsen, Jorgen and Friis, Soren: 2010 Full Text Ann. Neurol. 67 (5) 600 – 606: L-Type Calcium Channel blockers and Parkinson’s Disease in Denmark http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917467/?tool=pmcentrez
  5. Bagatini, P.B.; Saur, L.; Rodrigues, M. F.; Bernardino, G. C.; Paim. M. F.; Coelho, G. P.; Silva, DV.; de Oliveira, R. M.; Schirmer, H.; Souto, A A.; Vianna, M. and Xavier, L. L. (2011) Abstract Invert. Neurosci. 11 (1) 43-51: The role of calcium channel blockers and resveratrol in the prevention of paraquat-induced parkinsonism in Drosophila melanogaster: a locomotor analysis. http://www.ncbi.nlm.nih.gov/pubmed/21523449
  6. Ilijic, E.; Guzman J. N. and Surmeier, D. J.(2011) Abstract Neurobiol. Dis. 43 (2):364 - 371. The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease. http://www.ncbi.nlm.nih.gov/pubmed/21515375
  7. Rees, K.; Stowe, R.; Patel, S.; Ives, N.; Breen, K.; Ben-Shlomo, Y. and Clarke, C.E. (2011) Abstract Cochrane Database Syst. Rev. 9 (11) CD008535. Anti-hypertensive drugs as disease-modifying agents for Parkinson's disease: evidence from observational studies and clinical trials. http://www.ncbi.nlm.nih.gov/pubmed/22071852