Katelyn Sullivan

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and with case numbers rising dramatically each year, many scholars equate PD to a “noninfectious pandemic.”¹ The typical clinical manifestations include motor symptoms such as bradykinesia, shuffling gait, resting tremor, and cogwheel rigidity.¹ Commonly, non-motor symptoms present as well, such as anxiety and depression. PD is characterized pathologically by degenerated dopamine neurons in the substantia nigra pars compacta (SNc), of which a cause has not yet been discovered.²

Objective: As it currently stands, only symptomatic treatments exist that help lessen the classic motor findings, but do not address the underlying pathology.² Therefore, neuroprotective treatments are crucial to reverse the degeneration of the dopaminergic neurons in the SNc.

Search Methods: An online literature review in the PubMed database was conducted from 2017 to 2021 using the following keywords: “Parkinson’s disease,” “Isradipine,” “neuroprotection,” “L-type voltage-gated Ca²⁺ channels.”

Results: L-type voltage-gated Ca²⁺ channels (L-type VGCCs) are proposed to predispose the SNc dopaminergic neurons to vulnerability, and thus, degeneration via stressful oscillations and action potentials.³ Isradipine, classically used as an antihypertensive, has displayed potential as a neuroprotective treatment, acting by inhibiting L-type VGCCs.⁴ Isradipine was found to prevent upregulation of L-type VGCCs and prevent neuron depletion in the SNc in an experiment on mice with MPTP-induced impairment.⁴ The same study also found that isradipine prevented MPTP-induced motor coordination impairment as assessed by rotarod test.⁴ However, in a human trial isradipine was not proven to decrease the Unified Parkinson’s Disease Rating Scale (UPDRS), which is a metric that is based on several quality-of-life factors, especially motor complications.⁵ Therefore, isradipine is not considered to decrease motor symptoms or be neuroprotective. However, a new study reanalyzed the data from the human trial and found a sex-dependent significant correlation between levodopa equivalent dose required and isradipine.⁶ Higher isradipine exposure was mildly correlated with lower cumulative levodopa equivalent dose, but only for males; women revealed an opposite trend.⁶ Additionally, higher isradipine exposure correlated with a 13% decreased risk of requiring supplemental antiparkinson treatment compared to placebo.⁶

Conclusion: Based on the findings of the last study, L-type VGCC inhibitors should still be considered for further research as supportive medications in the treatment of PD. Isradipine and other L-type voltage-gated Ca²⁺ channels may be able to reduce the dosage of other antiparkinson medications and thus reduce side effects and improve quality of life.

Works Cited

1.  Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet. 2021;397(1021): 2284-2303.
2. Liss B, Striessnig J. The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson’s Disease. Annu Rev Pharmacol Toxicol. 2019;59(1): 263-289.
3. Sun Y, Zhang H, Selvaraj S, et al. Inhibition of L-Type Ca2+ channels by TRPC1-STIM1 complex is essential for the protection of dopaminergic neurons. J Neurosci. 2017;37(12):3364-3377.
4. Wang QM, Xu YY, Liu S, Ma ZG. Isradipine attenuates MPTP-induced dopamine neuron degeneration by inhibiting up-regulation of L-type calcium channels and iron accumulation in the substantia nigra of mice. Oncotarget. 2017;8(29): 47284-47295.
5. Parkinson Study Group STEADY-PD III Investigators. Isradipine versus placebo in early Parkinson disease: a randomized trial. Ann Intern Med. 2020; 172(9): 591-598.
6. Venuto CS, Yang L, Javidnia M, Oakes D, James Surmeier D, Simuni T. Isradipine plasma pharmacokinetics and exposure-response in early Parkinson’s disease. Ann Clin Transl Neurol. 2021;8(3):603-612. doi:10.1002/acn3.51300.