Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons

Abstract

Stress seems to contribute to Parkinson’s disease (PD) neuropathology, probably by dysregulation of the hypothalamic–pituitary–adrenal axis. Key factors in this pathophysiology are oxidative stress and mitochondrial dysfunction and neuronal glucocorticoid-induced toxicity. The insulin-like growth factor II (IGF-II), a pleiotropic hormone, has shown antioxidant and neuroprotective effects in some neurodegenerative disorders. Our aim was to examine the protective effect of IGF-II on a dopaminergic cellular combined model of PD and mild to moderate stress measuring oxidative stress parameters, mitochondrial and neuronal markers, and signalling pathways. IGF-II counteracts the mitochondrial-oxidative damage produced by the toxic synergistic effect of corticosterone and 1-methyl-4-phenylpyridinium, protecting dopaminergic neurons from death and neurodegeneration. IGF-II promotes PKC activation and nuclear factor (erythroid-derived 2)-like 2 antioxidant response in a glucocorticoid receptor-dependent pathway, preventing oxidative cell damage and maintaining mitochondrial function. Thus, IGF-II is a potential therapeutic tool for treatment and prevention of disease progression in PD patients suffering mild to moderate emotional stress.

Effects of Apamin on MPP+-Induced Calcium Overload and Neurotoxicity by Targeting CaMKII/ERK/p65/STAT3 Signaling Pathways in Dopaminergic Neuronal Cells

“…Several studies have suggested that reduction of TH, aggregation of αSYN, neuroinflammatory response, and apoptosis of dopaminergic neuronal cells play important roles in both in vitro and in vivo models of PD [ 6 , 12 , 47 , 48 ]. Thus, many studies have been conducted to find their inhibitors [ 7 , 10 , 47 , 49 , 50 , 51 , 52 , 53 ]. Furthermore, the membrane-permeable Ca 2+ chelator, BAPTA-AM, significantly protects cells from oxidative stress, ER stress, and apoptosis [ 22 , 54 , 55 , 56 ].…”

“…MPP + is then released and is specifically taken up by dopaminergic neurons via dopamine transporters, inhibiting the activity of mitochondrial complex I [ 5 ]. The consequences of mitochondrial dysfunction, thus induced by MPP + , are the inhibition of oxidative phosphorylation [ 6 ], ATP depletion [ 7 ], production of reactive oxygen species (ROS) [ 8 ], disturbance in calcium (Ca 2+ ) homeostasis [ 9 ], oxidative stress [ 10 ], explosive release of proinflammatory cytokines [ 11 ], mitochondrial depolarization, and permeability transition, which lead to apoptotic death of dopaminergic neurons [ 6 , 12 ].…”

IGF2-reprogrammed macrophages ameliorate the inflammatory response and protects against the neurodegenerative and neuroinflammatory process in Parkinson`s disease models.

“…Recently, the neuroprotective effect of recombinant IGF2 has been demonstrated by its interaction with IGF2R in PD cellular and animal models (MPTP/MPP+). In this pharmacological PD model, IGF2 prevented the mitochondrial dysfunction and the activation of nuclear factor (erythroid-derived 2)-like2 (NRF2) (55,96). Moreover, it was recently described that intranasal recombinant IGF2 administration ameliorated the dopaminergic neuronal loss induced by 6-OHDA models through IGF2R and IGF2R/PI3K/AKT signaling (97).…”

Trace Elements Open a New Direction for the Diagnosis of Atherosclerosis

“…Various neuropathological illnesses are associated with the increased production of glucocorticoids, which are crucial in controlling the biosynthesis and metabolism of proteins, lipids, and carbohydrates. Excessive ROS inappropriately accumulates and causes oxidative damage [128]. MnSOD is a significant antioxidant that can also remove superoxide produced in mitochondria and guard against oxidative stress [129,130].…”