alpha-synuclein and thymoquinone

Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive dopaminergic neurodegeneration with a concomitant increase in oxidative stress and neuroinflammation in the substantia nigra pars compacta (SNc). Recent studies have focused on targeting neuroinflammation and oxidative stress to effectively treat PD. The present study evaluated the neuroprotective effect of thymoquinone (TQ) against 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP)-induced oxidative stress and neuroinflammation in a PD mouse model. TQ (10 mg/kg body weight [b. wt.]) was administered for 1 week prior to MPTP (25 mg/kg b. wt.). MPTP administration caused oxidative stress as evidenced by decreased activities of superoxide dismutase and catalase, a depletion of reduced glutathione, and a concomitant rise in malondialdehyde. It also significantly increased pro-inflammatory cytokines and elevated inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Immunohistochemical analysis revealed dopamine neuron loss in the SNc and decreased dopamine transporters in the striatum following MPTP administration; however, these were rescued by TQ treatment. TQ treatment further restored antioxidant enzymes, prevented glutathione depletion, inhibited lipid peroxidation, and attenuated pro-inflammatory cytokines. TQ also decreased the raised levels of inflammatory mediators, such as COX-2 and iNOS. Therefore, TQ is thought to protect against MPTP-induced PD and the observed neuroprotective effects are attributed to its potent antioxidant and anti-inflammatory properties. Moreover, the in vitro analysis found that TQ significantly inhibited α-synuclein aggregation and prevented cell death induced by pre-formed fibrils. Thus, TQ not only scavenges the MPTP-induced toxicity but also prevents α-synuclein-fibril formation and its associated toxicity.

Topics: alpha-Synuclein; Animals; Benzoquinones; Cell Line, Tumor; Corpus Striatum; Humans; Male; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Parkinsonian Disorders; Protein Aggregates

The seeds of Nigella sativa are used worldwide to treat various diseases and ailments. Thymoquinone (TQ) that is present in the essential oil of these seeds mediates most of the plant's diverse therapeutic effects. The present study aimed to determine whether TQ protects against α-synuclein (αSN)-induced synaptic toxicity in rat hippocampal and human induced pluripotent stem cell (hiPSC)-derived neurons. Here, we report that αSN decreased the level of synaptophysin, a protein used as an indicator of synaptic density, in cultured hippocampal and hiPSC-derived neurons. However, simultaneous treatment with αSN and TQ protected neurons against αSN-induced synapse damage, as revealed by immunostaining. Moreover, administration of TQ efficiently induced protection in these cells against αSN-induced inhibition of synaptic vesicle recycling in hippocampal and hiPSC-derived neurons as well as against mutated P123H β-synuclein (βSN) in hippocampal neurons, as revealed by experiments using the fluorescent dye FM1-43. Using a multielectrode array, we further demonstrated that the treatment of hiPSC-derived neurons with αSN induced a reduction in spontaneous firing activity, and cotreatment with αSN and TQ partially reversed this loss. These results suggest that TQ protects cultured rat primary hippocampal and hiPSC-derived neurons against αSN-induced synaptic toxicity and could be a promising therapeutic agent for patients with Parkinson's disease and dementia with Lewy bodies.

Topics: Action Potentials; alpha-Synuclein; Animals; Benzoquinones; Cells, Cultured; Hippocampus; Humans; Induced Pluripotent Stem Cells; Mutation; Neurons; Neuroprotective Agents; Primary Cell Culture; Rats, Wistar; Synapses; Synaptic Vesicles; Synaptophysin

Topics: alpha-Synuclein; Animals; Benzoquinones; Hippocampus; Humans; Induced Pluripotent Stem Cells; Neurons; Neuroprotective Agents; Synapses