Synthesis of Melatonin Derivatives and the Neuroprotective Effects on Parkinson’s Disease Models of Caenorhabditis elegans

Abstract

Melatonin (MT) is a hormone with antioxidant activity secreted by the pineal gland in the human brain, which is highly efficient in scavenging free radicals and plays an important role in the neuro-immuno-endocrine system. Emerging evidence showed that MT supplementation was a potential therapeutic strategy for Parkinson’s disease (PD), which inhibits pathways associated with oxidative stress in PD. In this study, we reported a C7-selective olefination of melatonin under rhodium catalysis with the aid of PIII-directing groups and synthesized 10 new melatonin-C7-cinnamic acid derivatives (6a–6j). The antioxidant potential of the compounds was evaluated both by ABTS and ORAC methods. Among these newly synthesized melatonin derivatives, 6a showed significantly higher activity than MT at 10−5 M. In the transgenic Caenorhabditis elegans model of PD, 6a significantly reduces alpha-synuclein aggregation and dopaminergic neuronal damage in nematodes while reducing intracellular ROS levels and recovers behavioral dysfunction induced by dopaminergic neurodegeneration. Further study of the mechanism of action of this compound can provide new therapeutic ideas and treatment strategies for PD.

Melatonin restores endoplasmic reticulum homeostasis to protect injured neurons in a rat model of chronic cervical cord compression

“…The neuroprotective effect of melatonin has been shown in many CNS diseases 27,54,55 . In this study, we found that ischemic and hypoxic states cause ER stress, leading to neural apoptosis, whereas melatonin inhibits ER stress and improves neurological function (Figure 11).…”

“…The neuroprotective effect of melatonin has been shown in many CNS diseases. 27,54,55 In this study, we found that ischemic and hypoxic states cause ER stress, leading to neural apoptosis, whereas melatonin inhibits ER stress and improves neurological function (Figure 11). In an in vitro experiment, the application of an ER stress agonist indicated that melatonin protected neurons directly from anti-ER stress.…”

“…24,25 Melatonin is a potent free radical scavenger that has demonstrated beneficial effects in animal models of acute injuries, such as spinal cord injury (SCI), and chronic injuries, such as Parkinson's disease related to the CNS. [26][27][28][29][30] As a chronic nontraumatic SCI, we inferred that melatonin may be effective in treating CSM. In this in vivo experiment, we aimed to evaluate whether melatonin inhibited neuronal apoptosis by restoring ER homeostasis, alleviating ER stress, and promoting ERphagy, ultimately improving neurological function in a rat model of chronic cervical cord compression.…”

“…Melatonin is a potent free radical scavenger that has demonstrated beneficial effects in animal models of acute injuries, such as spinal cord injury (SCI), and chronic injuries, such as Parkinson's disease related to the CNS 26–30 . As a chronic nontraumatic SCI, we inferred that melatonin may be effective in treating CSM.…”

Design, Synthesis, and Neuroprotective Effects of Novel Cinnamamide-Piperidine and Piperazine Derivatives

“…These compounds display an array of pharmacological activities, including antioxidant properties, neuroprotection, antithrombotic effects, angiogenesis promotion, and vascular protective capacities. [19][20][21] These attributes suggest that cinnamic acid and its analogues could serve as promising lead compounds for stroke treatment.…”