Triptolide with potential medicinal value for diseases of the central nervous system

Abstract

Tripterygium wilfordii Hook.f. (TWHF) has a long history as a Traditional Chinese Medicine (TCM) herb that aids in treating inflammatory and autoimmune diseases. The major bioactive component of TWHF is triptolide, which has been recognized to possess a broad spectrum of biological profiles including antiinflammatory, immunosuppressive, antifertility, and antitumor activities, as well as neurotrophic and neuroprotective effects. Limitation of triptolide, such as poor water solubility and severe systemic toxicity, has postponed clinical development and trials; however, the wide range of medicinal value of triptolide has been drawing intensive worldwide attention. In particular, triptolide has been shown to have significant effects on central nervous system (CNS) diseases, such as Parkinson's disease, Alzheimer's disease, spinal cord and brain injury, and multiple sclerosis. This review focuses on the potential therapeutic role of triptolide on CNS diseases, and discusses the structural features, potential modifications, and the other pharmacological activities of triptolide.

Figure 1

The photograph of Tripterygium wilfordii Hook.f. and the structure of triptolide and its analogues.

Figure 2

The structure of (5R)‐5‐hydroxytriptolide (LLDT‐8).

Figure 3

Mechanisms of action of triptolide in the central nervous system. Neurotoxins including MMP ⁺, Aβ, glutamate, and H ₂ O ₂ can trigger microglial activation, release proinflammatory factors (PGE2, IL‐1β, tumor necrosis factor‐α [TNFα]) and reactive oxygen species (ROS) from activated microglia, activate receptors or transporters located on neuronal membranes, and may inhibit the neurotrophic activity of astrocytes. Triptolide (T10) was found to inhibit neuroinflammation and oxidative stress (①), stimulate the production and release of brain‐derived neurotrophic factor (BDNF) and NGF in astrocytes (②), prevent neuronal degeneration and apoptosis triggered by MPP ⁺ neurotoxicity (③), which is transported by dopamine transporters (DAT) from the extraneuronal space to the cytoplasm of the neuron, glutamate, and Aβ, which can make L‐type voltage‐sensitive calcium channels (L‐VSCCs) open, resulting in Ca²⁺ influx. In contrast, triptolide provides a neurotrophic effect on neurons by simulating BDNF and NGF production. As a result, neurons survive because of a decrease in ROS accumulation and Ca²⁺ overload, inhibition of mitochondrial dependent or independent apoptosis, which may be mediated by death receptors such as TNF receptor (TNF‐R), and the expression of target genes for survival.