Neuroprotective Effects of Safflower Flavonoid Extract in 6-Hydroxydopamine-Induced Model of Parkinson’s Disease May Be Related to its Anti-Inflammatory Action

Abstract

Safflower (Carthamus tinctorius. L.), a Chinese materia medica, is widely used for the treatment of cardiovascular and cerebrovascular diseases, with flavonoids being the major active components. Multiple flavonoids in safflower bind to Parkinson’s disease (PD)-related protein DJ-1. Safflower flavonoid extract (SAFE) improved behavioral indicators in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD; however, the underlying mechanisms remain unclear. We used a 6-OHDA-induced mouse model of PD and a primary neuron-astrocyte coculture system to determine the neuroprotective effects and mechanisms of SAFE. After three weeks of SAFE administration, behavioral indicators of PD mice were improved. SAFE regulated the levels of tyrosine hydroxylase (TH) and dopamine metabolism. It significantly inhibited the activation of astrocytes surrounding the substantia nigra and reduced Iba-1 protein level in the striatum of PD mice. SAFE reduced the plasma content of inflammatory factors and suppressed the activation of nod-like receptor protein 3 (NLRP3) inflammasome. In the coculture system, kaempferol 3-O-rutinoside and anhydrosafflor yellow B significantly improved neuronal survival, suppressed neuronal apoptosis, and reduced IL-1β and IL-10 levels in the medium. Thus, SAFE showed a significant anti-PD effect, which is mainly associated with flavonoid anti-inflammatory activities.

The Significance of NLRP Inflammasome in Neuropsychiatric Disorders

“…Ellagic acid (EA) harbors profound implications in protecting DA neurons by inhibiting NLRP3 inflammasome activation in the microglia [ 40 ]. Safflower flavonoid extract (SAFE) reduced the level of plasma inflammatory factors, inhibiting NLRP3 inflammasome activation in mice, exhibiting significant anti-Parkinson’s disease effects [ 41 ]. Naringin (NAR) inhibited microglial NLRP3 inflammasome signaling activation and pro-inflammatory factor release in rats and protected DA neuron viabilities in rats [ 42 ].…”

The circadian clock protein Rev-erbα provides neuroprotection and attenuates neuroinflammation against Parkinson’s disease via the microglial NLRP3 inflammasome

“…In addition, existing evidence shows extensive NLRP3 inflammasome activation in the SN of postmortem PD brains [ 11 ]. Neurotoxins such as MPTP, 6-OHDA, and αsyn PFF can induce the activation of the NLRP3 inflammasome [ 49 – 51 ], and inhibiting NLRP3 inflammasomes can effectively prevent dopaminergic neurodegeneration in PD models [ 51 , 52 ]. Consistent with the above research, we detected the activation of the NLRP3 inflammasome in the SN in the MPTP model, while the administration of SR9009 effectively inhibited NLRP3 inflammasome activation and the release of the inflammatory factors IL-1β and IL-18.…”

Cannabidiol Induces Autophagy to Protects Neural Cells From Mitochondrial Dysfunction by Upregulating SIRT1 to Inhibits NF-κB and NOTCH Pathways

“…PINK-1/Parkin pathway is related to mitochondrial damage ( Quinn et al, 2020 ), PINK1 promoted Parkin’s mitochondrial translocation and modification, thus protecting mitochondrial DNA from damage by reactive oxygen species and stimulating the self-repair process of mitochondria ( Xu et al, 2020 ). DJ-1 is a redox sensor of oxidative stress, upregulating DJ-1 antagonize the mitochondrial dysfunction caused by PINK1 mutation, thus, DJ-1 can be used as an important indicator of mitochondrial damage ( Lei et al, 2020 ). In the present study, we found that Cannabidiol pretreatment reduced MPP + -mediated mitochondrial damage via activation of PINK-1/parkin and DJ-1.…”