The Road to Repurposing a Drug: Isradipine

(D. James Surmeier, Northwestern University)

Definitions and concepts:

  • Case Study: Isradipine – dihydropyridine class molecule, use-dependent calcium channel antagonist; approved to treat hypertension, good safety profile

A selective increased vulnerability of a group of neurons is observed with multiple neurodegenerative diseases. Understanding and targeting that vulnerability may prove to be a valid therapeutic approach.

  • In Parkinson’s disease (PD), the dopaminergic neurons of the substantia nigra (SNc DA) are particularly affected and experience a very high degree of cell death.
  • In trying to understand the biology of these vulnerable neurons, it was discovered that these neurons function as slow autonomous pacemakers with regular firing. This regular firing pattern is associated with large calcium fluctuations in the dendritic and somatic compartments.
  • The calcium oscillations are due to L-type calcium channels.
    • Blocking these channels with isradipine completely prevents the dendritic calcium spikes without affecting the pacemaking firing, which is necessary for maintaining dopamine concentrations in the brain.
    • In particular, it is a calcium channel containing the Cav1.3 subunit that underlies the oscillations.
    • Cav1.3 channels are relatively rare in other types of neurons, making it an attractive drug target.
  • Sustained calcium fluctuations pose a significant metabolic burden on the neurons, which have to pump the calcium ions out of the cytoplasm against steep electrochemical gradients.
    • This metabolic burden ultimately leads to overproduction of free radicals that can damage the cell.
  • See Ref – Chan 2007.

Isradipine, a potent Cav1.3 antagonist with good brain bioavailability, is able to decrease oxidant levels in SNc DA neurons.

  • It also protects the neurons in chemical induced lesion models (6-OHDA) in a dose-dependent manner.
    • The serum concentrations required for neuroprotection are within the FDA guidelines for human dosing.
  • The use dependency of the drug confers cellular specificity – only channels in depolarized cells are preferentially antagonized.
  • Epidemiological data confirm that use of brain penetrant dihydropyridines are associated with a lower risk of PD (See REFS – Becker 2008, Ritz 2010).
  • Current phase II clinical trial with isradipine (DynaCirc) in early stage PD patients -

An understanding of the mechanisms underlying the selective vulnerability of neuron subpopulations will allow for novel therapeutic approaches to prevent neurodegeneration.

  • For PD, current clinical trials are underway to test creatine and Co-Q10 in decreasing levels of oxidative phosphorylation and the production of reactive oxygen species.
  • Isradipine targets an earlier component of the pathogenic pathway – a pharmacological “re-design” of vulnerable neurons could lower the metabolic rate and possibly slow disease pathogenesis.
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