Abstract
Parkinson’s disease (PD), a common adult-onset neurodegenerative disorder with complex pathological mechanisms, is characterized by the degeneration of dopaminergic nigrostriatal neurons. The present study demonstrated that the herbal medicines Hepad 1 and 2 protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity in C57BL/6 mice and SH-SY5Y cells. Hepad 1 and 2 remarkably alleviated the enhanced expression of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2, macrophage-1, and phosphorylated iκB-α) and apoptotic signals (Bcl-2-associated X protein, caspase-3, and poly [ADP-ribose] polymerase-1). Additionally, Hepad reduced MPTP-induced oxidative damage by increasing the expression of anti-oxidant defense enzymes (superoxide dismutase and glutathione S-transferase) and downregulating the levels of nicotinamide adenine dinucleotide phosphate oxidase 4. This study also showed that the neuroprotective effects of Hepad include anti-inflammatory, anti-apoptotic, and anti-oxidative properties, in addition to activation of the protein kinase B, extracellular-signal-regulated kinase, and c-Jun N-terminal kinase signaling pathways. Furthermore, oral administration of Hepad 1 and 2 attenuated the death of tyrosine hydroxylase-positive substantia nigra neurons that was induced by 20 mg/kg MPTP. Therefore, our results suggest that Hepad 1 and 2 are useful for treating PD and other disorders associated with neuro-inflammatory, neuro-apoptotic, and neuro-oxidative damage.
Highlights
Parkinson’s disease (PD) is caused by a deficiency of the neurotransmitter dopamine at the nerve terminals of nigrostriatal dopaminergic neurons in the striatum owing to the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) [1]
The cell viability was dramatically reduced in cells treated with 0.5 mM to 5 mM MPTP compared to untreated cells (Figure 1A); 1 and 2 mM MPTP, which caused significant cell death (29.05% and 68.89%, respectively), were selected to investigate the protective effects of Hepad 1 (H1) and Hepad 2 (H2) in subsequent experiments
We reported the apoptotic mechanisms by which Hepad exerts its protective effects in cell and animal PD
Summary
Parkinson’s disease (PD) is caused by a deficiency of the neurotransmitter dopamine at the nerve terminals of nigrostriatal dopaminergic neurons in the striatum owing to the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) [1]. Potential mechanisms underlying the pathogenesis of PD include disturbances in intracellular calcium homeostasis, the presence of exogenous and endogenous toxins, mitochondrial dysfunction, death of nigrostriatal dopaminergic neurons, oxidative stress, and cytotoxicity of reactive oxygen species (ROS) [1,3]. These factors are likely part of a complex network that leads to the death of dopaminergic neurons in PD [4]. Apoptotic death alters the expression of multiple genes, many of which are oncogenes; some of these oncogenes enhance the apoptotic process (e.g., Bcl2-associated X [Bax] and B-cell lymphoma [Bcl]-x), whereas others serve to inhibit the process (Bcl-2 and Bcl-xL) [8]. Neuroinflammation contributes to neurodegeneration and is thought to be primarily associated with overactive glial cells in the brains of patients with
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