Network pharmacology to elucidate the role of phytotherapy in neurocognitive disorders

To date, there are no entirely satisfactory drugs available to treat neurocognitive disorders. In light of the increasing incidences of these disorders in societies with aging populations, there is an urgent need to further improve treatment options.

Phytotherapy modulates diseases and symptoms by addressing multiple rather than single targets. Therefore, phytotherapy might be suited to treat complex diseases such as neurocognitive disorders.

We performed a systematic review of the literature with defined search terms using the PubMed database. The search terms were: [(network pharmacology) OR (systems pharmacology) OR (microarray) OR (proteomic) OR (metabolomic) OR (transcriptomic) OR (RNA-seq)] AND [Alzheimer) OR (dementia)]. These search strings were connected with [(herbal) OR (botanical)] for polyherbal formulations and [(phytochemical) OR (natural product)] for single-herb preparations. Systems biology focuses on the human organism as dynamic networks that cooperate in an orchestrated manner in the healthy as well as in the diseased body. The diseasome concept integrates disease phenotypes with hierarchical networks across various biological levels-organ networks, cellular networks, and signaling networks. Network pharmacology aims to interfere with such networks to treat complex, multifactorial diseases. Diseases may be caused by exposure to external factors harmful to health (exposomes). Phytotherapy might beneficially influence diseasomes thus restoring disturbed networks. Here, the "phytome" which integrates herbal drug ingredients into the exposome may be a rich source with which to counteract diseased networks.

Our literature search identified 642 hits. The final number of papers included was 41. Using sophisticated animal models (transgenic mice, injection of amyloid β fragments or specific chemicals, surgical interventions) conditions have been generated that resemble Alzheimer's disease, vascular dementia, and other types of dementia. Brain tissues (mainly hippocampus and cortex), blood serum, urine, and feces were investigated using metabolomic, proteomic, and transcriptomic methods. In these experimental dementia models, specific signaling networks were reported to be affected: they regulate pathophysiological mechanisms of inflammation, signal processing and transmission, neuroplasticity, vascular function and blood, cellular integrity and metabolism as well as cellular redox balance. About two dozen polyherbal formulations (mainly derived from traditional Chinese medicine) were used for treatment in these models and partially or fully restored not only the diseased networks (diseasomes) but also the disease symptoms. Another dozen mono-herbal preparations were used to treat dementia in experimental models, and similar beneficial effects were observed.

The selected 41 papers from the literature provided a good basis for a detailed analysis of the role of network pharmacology in understanding the multimodal modes of action of herbal preparations in neurocognitive disorders. Complex signaling networks add valuable new information to classical pharmacology. The understanding of phytopharmaceuticals' modes of action underpin the necessity to expand the search from classic pharmacological models to complex network interactions.