Impact of Silibinin A on Bioenergetics in PC12APPsw Cells and Mitochondrial Membrane Properties in Murine Brain Mitochondria

Abstract

Introduction: Age-related multifactorial diseases, such as the neurodegenerative Alzheimer’s disease (AD), still remain a challenge to today’s society. One mechanism associated with AD and aging in general is mitochondrial dysfunction (MD). Increasing MD is suggested to trigger other pathological processes commonly associated with neurodegenerative diseases. Silibinin A (SIL) is the main bioactive compound of the Silymarin extract from the Mediterranean plant Silybum marianum (L.) (GAERTN/Compositae). It is readily available as a herbal drug and well established in the treatment of liver diseases as a potent radical scavenger reducing lipid peroxidation and stabilize membrane properties. Recent data suggest that SIL might also act on neurological changes related to MD. Methods: PC12APPsw cells produce low levels of human Aβ and thus act as a cellular model of early AD showing changed mitochondrial function. We investigated whether SIL could affect mitochondrial function by measuring ATP, MMP, as well as respiration, mitochondrial mass, cellular ROS and lactate/pyruvate concentrations. Furthermore, we investigated its effects on the mitochondrial membrane parameters of swelling and fluidity in mitochondria isolated from the brains of mice. Results: In PC12APPsw cells, SIL exhibits strong protective effects by rescuing MMP and ATP levels from SNP-induced mitochondrial damage and improving basal ATP levels. However, SIL did not affect mitochondrial respiration and mitochondrial content. SIL significantly reduced cellular ROS and pyruvate concentrations. Incubation of murine brain mitochondria with SIL significantly reduces Ca2+ induced swelling and improves membrane fluidity. Conclusions: Although OXPHOS activity was unaffected at this early stage of a developing mitochondrial dysfunction, SIL showed protective effects on MMP, ATP- after SNP-insult and ROS-levels in APPsw-transfected PC12 cells. Results from experiments with isolated mitochondria imply that positive effects possibly result from an interaction of SIL with mitochondrial membranes and/or its antioxidant activity. Thus, SIL might be a promising compound to improve cellular health when changes to mitochondrial function occur.

Role of traditional Chinese medicine in ameliorating mitochondrial dysfunction via non-coding RNA signaling: Implication in the treatment of neurodegenerative diseases

“…Recent studies reported that silibinin alleviated motor dysfunction in a PD mouse model by inhibiting oxidative stress, neuroinflammation, and imbalance of mitochondrial dynamics and promoting mitophagy and mitochondrial biogenesis (Liu et al, 2021b;Liu et al, 2021c). In an in vivo AD model, the silibinin intervention significantly reduced the Ca 2+ overload-induced mitochondrial swelling and improved the fluidity of the mitochondrial membrane (Esselun et al, 2021).…”

The Role of a Pathological Interaction between β-amyloid and Mitochondria in the Occurrence and Development of Alzheimer’s Disease

“…В качестве другого перспективного соединения можно рассмотреть флавоноид силибинин (силибин), обладающий антиоксидантной активностью [181]. Силибинин взаимодействует с митохондриальной мембраной, препятствуя дисфункции изолированных митохондрий [182] [190]. Кверцетин уменьшает дисфункцию митохондрий, снижая образование АФК, восстанавливая потенциал митохондриальной мембраны и синтез ATP; регулирует экспрессию AMP-активируемой протеинкиназы (AMPK), которая участвует в модулировании энергетического метаболизма; снижает отложение Aβ, способствует его выведению и регулирует процессинг APP [191].…”

“…Another promising compound is the flavonoid silibinin (silybin), which has antioxidant activity [ 181 ]. Silibinin interacts with the mitochondrial membrane, preventing the dysfunction of isolated mitochondria [ 182 ]. Administration of silibinin decreases the MDA level and increases the activity of the antioxidant enzymes CAT, SOD, nitric oxide (NO), and glutathione (GSH) [ 183 , 184 , 185 , 186 ].…”