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

Abstract

The aim of this study is to investigate the effects of L-type calcium channels (LTCCs) on MPTP-induced dopamine (DA) neuron degeneration and iron accumulation in the substantia nigra (SN) of mice. By real-time PCR and western blots, we first quatified expressions of L-type Cav1.2 and Cav1.3 calcium channel α1 subunits in the SN of experimental mice treated with MPTP. We found that the expressions of Cav1.2 and Cav1.3 calcium channel α1 subunits markedly increased after MPTP treatment for 2 and 3 weeks. Secondly, we observed the effects of isradipine, a LTCC antagonist, on MPTP-induced DA neuron degeneration and iron accumulation in the SN. Our results showed that isradipine treatment prevented against MPTP-induced Cav1.2 and Cav1.3 calcium channel α1 subunits up-regulation in the SN. We also found that isradipine prevented against MPTP-induced DA neuron depletion in the SN and partly restored the DA content in the striatum. Moreover, we found that isradipine inhibited the increase of iron positive cells in the SN of the MPTP-treated mice. Finally, we investigated the effects of isradipine on cellular iron accumulation in the dopaminergic MES23.5 cell line. Our studies showed that MPP+ treatment accelerated iron influx in the MES23.5 cells. Treatment with Bayk8644 further aggravated iron accumulation. Treatment with isradipine prevented against MPP+-induced iron influx in the MES23.5 cells. These results suggest that up-regulation of LTCCs may be responsible for the DA neuron degeneration in the MPTP-treated mice, The LTCCs may directly contribute to iron influx into DA neurons, and isradipine may suppress cellular iron accumulation and prevents neurodegeneration.

Redox Mechanisms in Neurodegeneration: From Disease Outcomes to Therapeutic Opportunities

“…Increased expression of Ca v 1.3 in early-stage PD, before the appearance of pathological changes, also suggests the disruption of Ca 2+ homeostasis (233). Consistent with these findings, isradipine, an l-type Ca 2+ channel blocker, which is now in clinical trials, prevents cell death of mouse DA neurons, challenged with a-synuclein, MPTP, or 6-hydroxydopamine (6-OHDA) (82,237,527). In addition to these mechanisms, Ca 2+ dysregulation contributed by intracellular stores, such as the ER and mitochondria, has been implicated (71, 560).…”

The Role of Oxidative Stress in Parkinson’s Disease

“…This distribution in calcium channel may explain why DAergic neurons in SN are more susceptible to oxidative stress or excitotoxicity. Isradipine, an L-type calcium channel blocker, demonstrates protective effects against α-synuclein, 6-hydroxydopamine (6-OHDA) or MPTP-induced neurotoxicity in DAergic neurons [ 29 , 30 , 31 ], supporting the association between calcium influx through L-type CA 2+ channels and PD pathogenesis.…”

Calcium, Bioenergetics, and Parkinson’s Disease

“…PD-linked mutations in leucine-rich repeat kinase 2 (LRRK2, PARK-8) increase the expression of MCU and MICU1 [ 302 ] and decrease mitochondrial Ca 2+ efflux [ 303 ]. In zebrafish, inhibition of mitochondrial Ca 2+ influx protects neurons against the effects of mutations mimicking the functional effects of those seen in PD patients [ 304 , 305 ], just as does inhibition of Cav1 Ca 2+ channels responsible for mitochondrial Ca 2+ influx in rodent SN DAergic neurons [ 102 , 105 , 306 , 307 , 308 , 309 , 310 ].…”