Baicalein Protects against Rotenone-Induced Neurotoxicity through Induction of Autophagy

Abstract

Baicalein, a typical flavonoid compound, has neuroprotective properties in several neurological disorders. Autophagy plays a central role in maintaining the cellular homeostasis, and is involved in the pathogenesis of Parkinson's disease (PD). Recently, baicalein has been reported to induce autophagy. Therefore, the current study was designed to investigate whether baicalein could protect against rotenone-induced neurotoxicity via induction of autophagy both in SH-SY5Y cells and in a mouse model. A chronic PD mouse model was established by continuous intragastric administration of rotenone for 12 weeks. Baicalein was administrated from 7 to 12 week. Our results showed that baicalein prevented rotenone-induced behavioral deficits, dopaminergic neuronal loss, apoptosis and mitochondrial dysfunction. Furthermore, baicalein restored rotenone-impaired autophagy, and blocking the baicalein-induced autophagy using 3-methyladenine inhibited the neuroprotective effects of bacalein. Baicalein increased cell viability and restored mitochondrial function in SH-SY5Y cells. The beneficial effect of baicalein was abrogated by 3-methyladenine treatment. Furthermore, rapamycin increased autopahgy and reduced the rotenone-induced neurotoxicity in SH-SY5Y cells. Collectively, these results suggest that baicalein could prevent rotenone-induced neurotoxicity via restoring autophagy. Key words baicalein; neuroprotection; Parkinson's disease; autophagyParkinson's disease (PD) is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, and postural instability.1-3) The main pathological characteristic of PD is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, the loss of dopamine in the striatum, and the presence of intracytoplasmic inclusions in surviving neurons known as Lewy bodies.4) Several biochemical mechanisms related to the pathogenesis of PD include oxidative stress, mitochondrial dysfunction, protein aggregation and misfolding, apoptosis, excitotoxicity, and neuroinflammation.5,6) Currently, none of therapies has been convincingly shown to slow down or prevent the progression of PD, and additional effective treatments for this disease are urgently needed.Baicalein, a flavonoid, is derived from the root of the traditional Chinese herb Scutellariabaicalensis GEORGI. Baicalein has been reported to have neuroprotective effects in PD model through anti-inflammatory, anti-apoptosis, and anti-oxidative actions. In vitro, baicalein protected PC12 cells against 6-hydroxydopamine (6-OHDA)-or rotenone-induced neurotoxicity, 7,8) and ameliorated the 6-OHDA-induced SH-SY5Y cell apoptosis.9) In vivo, baicalein exerted neuroprotective effects in 6-OHDA-induced neurotoxicity in rats 9) and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice.10) However, the exact mechanism of baicalein is poorly understood.Autophagy is a highly conservative cellular process by which cells degrade and recycle of bulk cytosolic proteins and dama...

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation

“…In turn, flavonoids can be sub-classified into flavonols, flavones, flavanols, flavanones, anthocyanidins, and isoflavonoids, according to the structure of the heterocycle C ring. Examples of compounds which are mostly investigated for their potential neuroprotective effects include quercetin, kaempferol and myricetin (flavonols) [ 50 , 51 , 52 , 53 , 54 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ], scutellarin, baicalein, and apigenin (flavones) [ 50 , 55 , 56 , 61 , 87 , 88 , 89 , 90 ], catechins, epicatechin, and epigallocatechin gallate (EGCG, flavanols), as well as genistein (isoflavonoid), and silymarin (flavonolignan) [ 63 , 91 , 92 , 93 , 94 , 95 , 96 ]. The stilbene group is best exemplified by resveratrol, a well-known phenolic compound found in red wine, grape, and virgin olive oil, which has shown remarkable neuroprotective and anti-aging properties in a plethora of experimental models [ 50 , 58 , 59 , 65 , 69 , 97 , 98 , 99 , 100 , 101 , 102 ].…”

“…As shown in various experimental models of neurodegeneration, a failure in the autophagy machinery may predispose to neuronal injury due to extreme oxidative damage intermingling with protein overload and neuroinflammation, while rescuing autophagy may confer protection to grant cell survival [ 7 , 10 , 21 , 24 , 28 , 29 ]. It is remarkable that a wide variety of phytochemicals, including phenolic compounds such as anthocyanins, stilbenes (resveratrol), monophenols (caffeic acid, gallic acid), glucosides and flavonoids (catechin, epicatechin, quercetin, myricetin), and also nitrogen-containing compounds (berberine and spermine), are capable of stimulating autophagy to confer neuroprotection through either Akt/mTOR inhibition or AMPK/SIRT1 or TFEB activation [ 3 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. Thus, in the next section, we discuss evidence bridging the antioxidant effects of these compounds with autophagy-related neuroprotection.…”

“…The combination of catechin and quercetin, through upregulation of PGC-1α, results in a synergistic improvement in neuronal mitochondrial function and cytoprotection against ischemic injury [ 178 ]. Again, in in vitro and in vivo models of mitochondrial toxin-induced PD, phytochemicals such as kaempferol and baicalein provide anti-apoptotic and antioxidant neuroprotective effects through the enhancement of mitochondrial turnover by autophagy, which is abolished when autophagy is pharmacologically inhibited [ 52 , 55 ]. These effects are also reported for bacosides/bacopasides, which induce Parkin-dependent mitophagy to exert anti-senescence and anti-apoptotic effects [ 71 ].…”

“…In this frame, it is remarkable that the common neuroprotective, antioxidant, and anti-inflammatory effects produced by several phytochemicals are associated with rescuing autophagy, meanwhile counteracting behavioral alterations, mitochondrial damage as well as intracellular accumulation and release of potentially detrimental substrates [ 3 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. As recently reviewed, the neuroprotective effects of phytochemicals involve also a double-faceted, yet controversial modulation of the proteasome pathway, which will not be discussed in detail herewith [ 9 ].…”

Targeting Cellular Stress Mechanisms and Metabolic Homeostasis by Chinese Herbal Drugs for Neuroprotection

“…Studies have demonstrated that autophagy is also involved in the pathogenesis of PD. Baicalein, hederagenin, carnosic acid, sulforaphane, piperine, triptolide, conophylline, and resveratrol [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ] significantly upregulate autophagy to prevent behavioral deficits, attenuate dopaminergic neuronal loss, neuronal apoptosis, and mitochondrial dysfunction, suppress oligomerized α-synuclein, and restore the interactions of parkin and beclin-1 via the AMPK-mTOR signaling cascade and heme oxygenase-1, LC3II, and p62 signaling. In contrast, oleuropein, baicalein, and cucurbitacin E decreased neuronal death and autophagic flux by inhibiting autophagic initiation in 6-OHDA or MPP + -infused substantia nigra (SN) PD models [ 53 , 61 , 62 ].…”