Neuroprotective Effect of Chlorogenic Acid on Mitochondrial Dysfunction-Mediated Apoptotic Death of DA Neurons in a Parkinsonian Mouse Model

Abstract

Mitochondrial dysfunction and oxidative stress characterize major factors involved in the activation of complex processes corresponding to apoptosis-mediated neuronal senescence of dopaminergic neurons (DA) in Parkinson’s disease (PD). Here, we evaluated the molecular mechanisms participating in the treatment of a 1-methyl-4-phenyl-1,2,3,6-tetrahydopyridine- (MPTP-) intoxicated PD mouse model in response to chlorogenic acid (CGA). The results indicate that CGA treatment significantly improved the motor coordination of the MPTP-intoxicated mice. CGA also alleviated the fall in activity of mitochondrial complexes I, IV, and V in accordance with ameliorating the level of superoxide dismutase and mitochondrial glutathione in the midbrain of MPTP-induced mice. CGA inhibited the activation of proapoptotic proteins including Bax and caspase-3, while elevating the expression of antiapoptotic protein like Bcl-2 consequently preventing the MPTP-mediated apoptotic cascade. The study also revealed the improved phosphorylation state of Akt, ERK1/2, and GSK3β which was downregulated as an effect of MPTP toxicity. Our findings signify that CGA may possess pharmacological properties and contribute to neuroprotection against MPTP induced toxicity in a PD mouse model associated with phosphorylation of GSK3β via activating Akt/ERK signalling in the mitochondrial intrinsic apoptotic pathway. Thus, CGA treatment may arise as a potential therapeutic candidate for mitochondrial-mediated apoptotic senescence of DA neurons in PD.

Beneficial Effects of Epigallocatechin-3-O-Gallate, Chlorogenic Acid, Resveratrol, and Curcumin on Neurodegenerative Diseases

“…CGA reduced the drug-induced neuroinflammation in substantia nigra by regulating the NF-κB expression and release of certain pro-inflammatory mediators such as TNF-α and interleukin (IL)-1β with the enhanced expression of anti-inflammatory cytokine IL-10. The similar experiments also demonstrated that CGA inhibited the activation of proapoptotic proteins including B-cell lymphoma-2 (Bcl-2) associated X protein (Bax) and caspase-3 and elevated the expression of antiapoptotic protein like Bcl-2 to prevent apoptosis [ 127 ]. CGA improved phosphorylation state of Akt, ERK1/2, and GSK-3 β which was downregulated as an effect of the drug-induced toxicity.…”

Therapeutic Role of Protein Tyrosine Phosphatase 1B in Parkinson’s Disease via Antineuroinflammation and Neuroprotection In Vitro and In Vivo

“…Daveri et al also reported that cyanidin and delphinidin modulated the inflammation process through the attenuation of PTP1B and downregulation of NF- κ B [ 62 ]. Many studies also discussed the attenuation of inflammation may benefit PD progression in in vitro and in vivo models [ 63 – 67 ]. Moreover, Xu et al demonstrated that punicalagin could promote M2 polarization of the macrophage by PTP1B blocking [ 68 ].…”

Neuroprotective Effects of Coffee Bioactive Compounds: A Review

“…In rotenone-injected mice, chlorogenic acid ameliorated degeneration of dopaminergic neurons in the substantia nigra and upregulated the antioxidative molecules–metallothionein-1 and 2, in striatal astrocytes [ 321 ]. In the study by Singh et al [ 322 ], chlorogenic acid improved motor coordination and neurobehavioral activity in the MPTP-induced model of Parkinson’s disease in mice. Of note, the behavioral effects were accompanied by reduced degeneration of dopaminergic neurons in the substantia nigra.…”

“…Moreover, chlorogenic acid improved mitochondrial function, suppressed ROS generation, increased SOD and mitochondrial GSH activity, inhibited activation of proapoptotic proteins (Bax and caspase-3), and elevated expression of the anti-apoptotic protein (Bcl2). Since it improved the phosphorylation state of Akt, ERK1/2, and GSK3β, it appears that the neuroprotective effects of chlorogenic acid against MPTP-induced neurotoxicity are mediated, at least in part, by the GSK3β phosphorylation-associated Akt/ERK pathway [ 322 ]. It is also worth noticing that chlorogenic acid attenuated the extensive release of release of TNF-α and IL-1β in the substantia nigra of the LPS-injected mice suggesting that this compound may suppress inflammatory response or damage in neurodegenerative diseases including Parkinson’s disease [ 323 ].…”