Rotenone-induced energy stress decompensated in ventral mesocerebrum is associated with Parkinsonism progression in rats

Abstract

Abstract. Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is characterized by the hallmark feature of loss of dopaminergic neurons in the substantia nigra. Energy metabolic disorder is associated with the pathogenesis of PD; however, the development of this disorder is yet to be elucidated. PD-like characteristics have been demonstrated in a rotenone rat model. In the present study, energy metabolism status was investigated in a rat model following intraperitoneal treatment with 1.0 mg/kg rotenone every 48 h. The behavior and tyrosine hydroxylase-positive levels in the substantia nigra of rats that were treated with rotenone for 24 weeks demonstrated that these rats developed more severe parkinsonism, as compared with that were treated for 16 weeks. Detection of ATP, lactic acid, NADH dehydrogenase 1 mRNA and lactate dehydrogenase B mRNA levels in the ventral mesocerebrum (VM) and skeletal muscle (SM) of the rats that had been treated with rotenone for 16 and 24 weeks demonstrated that the energy stress induced by rotenone progressed in both VM and SM. Notably, the energy stress detected in VM was more severe, and this energy stress was decompensated in the VM of rats that had been treated with rotenone for 24 weeks. The progression of energy stress and the incidence of energy decompensation in VM may be important for the improvement of PD pathology. IntroductionParkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra. PD is the most common neurodegenerative movement disorder, affecting >1% of the population that are aged >60 (1). Current treatments, such as pharmaceutical agents or deep brain stimulation predominantly target the symptoms and are unable to attenuate or reverse the progression of this disease (2). Understanding PD at a cellular and molecular level is important to determine novel targets and develop neuroprotective and disease-modifying therapeutic strategies. Although the causes and potential factors remain unknown, environmental factors may have a critical role, such as herbicides or pesticides, organic solvents, carbon monoxide and carbon disulfide (3,4). Notably, various studies have suggested that PD is associated with energy metabolism defects (5-7).Due to their structure, physiologic activities and high oxidative level of DA metabolism, DA cells in the substantia nigra are energy demanding and prone to energy stress (8). Furthermore, these cells have a relative low capacity for glycolysis compensation and lower glutathione levels (9,10), which ensures that they cannot respond appropriately to energy stress and are thus sensitive to energy disturbances.Rotenone is a common insecticide and mitochondria complex 1 inhibitor, which is used to induce chronic rotenone rat models with PD-associated features that manifest as DA cells are selectively damaged (11). However, how energy stress is induced and associated with the development of PD-associated in this model remains unknown.In the present study, rats were ...

Repaglinide Elicits a Neuroprotective Effect in Rotenone-Induced Parkinson’s Disease in Rats: Emphasis on Targeting the DREAM-ER Stress BiP/ATF6/CHOP Trajectory and Activation of Mitophagy

“…In the current study, we used the rotenone model, a well-developed model for inducing PD in rats as previously reported. − Rotenone induces neurodegeneration in the SNpc resulting in involuntary movement disorders and loss of muscular grip power, similarly, as presented in the late stages of PD patients . This study recapitulates the microscopic abnormalities, cognitive dysfunction, and behavioral deficits as seen in the rotenone-treated group.…”

“…These results can be explained on the basis of rotenone’s ability to evoke mitochondrial energy stress due to the inhibition of complex I in the electron transport chain. This results in the detrimental production of reactive oxygen species (ROS) as a compensatory mechanism, an imperative driver of apoptosis, ER stress, and α-synuclein aggregation. ,, On the contrary, repaglinide profoundly increased the SNpc viable neuronal count compared with the untreated group, demonstrating its neurorestorative effect.…”

“…This results in the detrimental production of reactive oxygen species (ROS) as a compensatory mechanism, an imperative driver of apoptosis, ER stress, and αsynuclein aggregation. 24,27,28 On the contrary, repaglinide profoundly increased the SNpc viable neuronal count compared with the untreated group, demonstrating its neurorestorative effect.…”

Metabolomics analysis highlights Yashtimadhu (Glycyrrhiza glabra L.)‐mediated neuroprotection in a rotenone‐induced cellular model of Parkinson's disease by restoring the mTORC1‐AMPK1 axis in autophagic regulation

“…The rotenone‐mediated inhibition of the mitochondrial complex‐I (Li et al, 2003) and the decreased NADH reduced the efficiency of ETC. The reduced output of ETC subsequently leads to reduced ATP levels and establishing energetic stress due to rotenone (Bai et al, 2016).…”