L-Ornithine L-Aspartate Restores Mitochondrial Function and Modulates Intracellular Calcium Homeostasis in Parkinson’s Disease Models

Abstract

The altered crosstalk between mitochondrial dysfunction, intracellular Ca2+ homeostasis, and oxidative stress has a central role in the dopaminergic neurodegeneration. In the present study, we investigated the hypothesis that pharmacological strategies able to improve mitochondrial functions might prevent neuronal dysfunction in in vitro models of Parkinson’s disease. To this aim, the attention was focused on the amino acid ornithine due to its ability to cross the blood–brain barrier, to selectively reach and penetrate the mitochondria through the ornithine transporter 1, and to control mitochondrial function. To pursue this issue, experiments were performed in human neuroblastoma cells SH-SY5Y treated with rotenone and 6-hydroxydopamine to investigate the pharmacological profile of the compound L-Ornithine-L-Aspartate (LOLA) as a new potential therapeutic strategy to prevent dopaminergic neurons’ death. In these models, confocal microscopy experiments with fluorescent dyes measuring mitochondrial calcium content, mitochondrial membrane potential, and mitochondrial ROS production, demonstrated that LOLA improved mitochondrial functions. Moreover, by increasing NCXs expression and activity, LOLA also reduced cytosolic [Ca2+] thanks to its ability to modulate NO production. Collectively, these results indicate that LOLA, by interfering with those mitochondrial mechanisms related to ROS and RNS production, promotes mitochondrial functional recovery, thus confirming the tight relationship existing between cytosolic ionic homeostasis and cellular metabolism depending on the type of insult applied.

Anti-miRNA103/107 encapsulated in transferrin-conjugated lipid nanoparticles crosses blood-brain barrier and reduces brain ischemic damage

“…Cortical neurons were first exposed to OGD for 3 h and then to reoxygenation for 24 h. 27 , 28 In brief, the culture medium was replaced with a hypoxia medium, which was previously saturated with 95% N 2 and 5% CO 2 for 20 min; it contained NaCl 116 mM, KCl 5.4 mM, MgSO 4 0.8 mM, NaHCO 3 26.2 mM, NaH 2 PO 4 1 mM, CaCl 2 1.8 mM, glycine 0.01 mM, and 0.001 w/v phenol red. Hypoxic conditions were maintained with a hypoxia chamber (temperature 37°C, atmosphere 95% N 2 , and 5% CO 2 ).…”

“…Mitochondrial function was assessed by measuring the level of mitochondrial dehydrogenase activity using the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5, diphenyltetrazolium bromide (MTT) as substrate. 28 The assay is based on the ability of living mitochondria to convert dissolved MTT into insoluble formazan. Briefly, after treatments, the medium was removed, and the cells were incubated in 500 μM of MTT solution (0.5 mg/mL) for 1 h in a humidified 5% CO 2 incubator at 37°C.…”

Deletion of Calhm2 alleviates MPTP-induced Parkinson's disease pathology by inhibiting EFHD2-STAT3 signaling in microglia

“…PINK1 deficiency causes mitochondrial accumulation of calcium, resulting in mitochondrial calcium overload [20]. L-Ornithine L-Aspartate was found to slow the progression of PD by regulating intra-mitochondrial calcium homeostasis and restoring mitochondrial function in a PD model [21]. Additionally, Rifampicin has been found to reduce neuroinflammation by reducing mitochondrial dysfunction due to impaired calcium homeostasis in PD [22].…”