Neuroprotective Effect of Kaempferol against a 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Mouse Model of Parkinson's Disease

Abstract

Parkinson's disease (PD) is a progressive, age-related, neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor and gait disturbance 1) ; it occurs in 1-2% of the population over the age of 60 years.2) Typical neuropathologic features of the disease are dopaminergic neuron degeneration in the substantia nigra and the presence of eosinophilic intracytoplasmic inclusions (Lewy bodies) in the residual dopaminergic neurons. The most widely used mouse model of PD is produced by systemically administering the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).3) MPTP is converted by monoamine oxidase B (MAO-B) to 1-methyl-4-phenylpyridinium (MPP ϩ ), which is a neurotoxic metabolite and could block cellular respiration, promote reactive oxygen species (ROS) formation, and cause neuronal death. 4,5) Oxidative stress has been implicated either as the cause or as a consequence of the pathogenetic mechanisms responsible for neurodegenerative disease, including PD. Indeed, the brain is prone to producing ROS and oxidative stress, due to its high metabolic rate, combined with the high content of oxidizable molecules, such as dopamine and neuromelanin, whose metabolism generates ROS. [6][7][8] Superoxide dismutase (SOD) is one of the key enzymes that provide the first line of defense against pro-oxidants. Glutathione peroxidase (GSH-PX) is thought to play an important role in protecting membranes from damage due to lipid peroxidation. The major detoxification function of GSH-PX is the termination of radical chain propagation by quick reduction to yield further radicals.9) The levels of SOD and GSH-PX activity reflect the ability of organism to eliminate free radicals. Malondialdehyde (MDA) is the end product of lipid peroxidation, and its level could indirectly reflect the metabolic degree of oxygen radicals, thus serving as an index of oxidative damage. 10)Kaempferol is a prototype member of the flavonol subclass of flavonoids, which is widely found in tea, broccoli, grapefruit, brussel sprouts and apple and is claimed to have strong antioxidant and anti-inflammatory properties. 11)Kaempferol, can be given orally, is absorbed well and the bioavailability is proportionate to its dose.12) Kaempferol had earlier been shown to afford efficient neuroprotection against several apoptosis and necrosis-inducing insults, such as oxidized low-density lipoproteins 13,14) and L-glutamate. 15,16)Ishige et al. 15) demonstrated that kaempferol efficiently blocked the increase in ROS associated with the oxidative stress caused by glutamate in the mouse hippocampal cell line demonstrated that kaempferol exerted a strong and prolonged protective effect against rotenone toxicity, which was a classical toxin inducing PD. Striatal glutamatergic response of rat brain slices was also preserved by kaempferol, posing a more general protection of kaempferol in PD.Preliminary studies in our laboratory have shown that kaempferol derivatives prevent oxidative stress-induced cell death in a DJ-1-dependent manner in...

Anti-Parkinsonian drug discovery from herbal medicines: What have we got from neurotoxic models?

“…In 6-OHDA-treated rats, quercetin enhanced spatial memory (Sriraksa et al, 2012) while myricetin suppressed iron toxicity . In MPP + /MPTP models, quercetin and myricetin were effective in vitro (Mercer et al, 2005;Zhang et al, 2011a) and kaempferol was reported to be effective in vivo (Li and Pu, 2011). In the rotenone models, however, only kaempferol showed positive effect against rotenone toxicity in SH-SY5Y cells.…”

Recent trends in the development of nanophytobioactive compounds and delivery systems for their possible role in reducing oxidative stress in Parkinson’s disease models

“…223 Kaempferol has a neuroprotective effect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in a mouse PD model. 224 However, bioavailability is limited to approximately 2% after oral administration. 225 Nanosized kaempferol enhances the antioxidant activity of kaempferol.…”

Cytoprotective Effect of Kaempferol on Paraquat-Exposed BEAS-2B Cells <i>via</i> Modulating Expression of <i>MUC5AC</i>

“…KM has been highlighted over the past years due to its multifunctional efficacies in various diseases such as Parkinson's disease and cancer. [33][34][35] It has been deemed as a drug for the management of inflammatory processes of airway diseases due to its potent anti-inflammatory and antioxidant characteristics. [33][34][35] In addition, other studies have also been demonstrated that KM can block not only lipopolysaccharideinduced NF-κB signaling but also suppress stress-induced MUC expression.…”

“…[33][34][35] It has been deemed as a drug for the management of inflammatory processes of airway diseases due to its potent anti-inflammatory and antioxidant characteristics. [33][34][35] In addition, other studies have also been demonstrated that KM can block not only lipopolysaccharideinduced NF-κB signaling but also suppress stress-induced MUC expression. 31,36,37) However, the beneficial effects of KM on PQ-mediated ROS stress in BEAS-2B cells have not been well elucidated yet.…”