Withanolide

The Substance: Withanolides can be found in the Indian herbal medicine Ashwagandha. Ashwagandha is a powder derived from the root of the plant of the same name. Withanolides are currently being explored for their brain regenerative properties.

Medicinal Properties:

• suppresses free radical generation;
• anti-inflammatory;
• suppresses cancer cell proliferation accompanied by apoptosis through inhibiting NFkappaB.
• induces significant regeneration of axons, dendrites, pre-synapses and post-synapses in the brains of mice.
• ameliorates neuronal dysfunction in mice with Alzheimer's disease.

• Synonyms for Ashwagandha:
  • Latin name: Withania Somnifera;
  • English name: Winter Cherry; Indian Ginseng.
• Steroidal lactones characterised by ergostane type steroids with a C28 basic skeleton with a side chain of C9 units of which a six-membered lactone ring is a characteristic feature.
• Molecular Withanolide: C28 H46 O2.
• For brain cells the focus is on the following constituents: withanolide A, withanoside IV, and withanoside VI;
• Metabolite: Sominone.
• Extraction: isolated from fresh roots.

• Family: Solanaceae
  
• Genus: Withania
  
• Species: Withania Somnifera (Dunal)

  Ashwagandha (Withania Somnifera) is a plant from the Solanaceae or Nightshade family which includes the Potatoe, Tomato and Deadly Nightshade species.

  It grows as a stout shrub that reaches a height of 170cm. Like the tomato, ashwagandha bears yellow flowers and red fruit, though its fruit has the size and shape of a berry. Ashwagandha grows abundantly in India, Pakistan, and Sri Lanka.

Historical Uses:
The leaves and berries of Ashwagandha have been in use for centuries in India. The extract is an important part of Indian Ayurvedic medicine. It has been used in the following ways:

• Coagulent: the berries are used as a substitute for rennet, to coagulate milk in cheese making;
• Sedative: the species name somnifera means "sleep-bearing" in Latin;
• Sexual vitality;
• General tonic and "adaptogen", helping the body adapt to stress;
• Liver tonic;
• Anti-inflammatory agent.

Availability: the withanolide content of ashwagandha is now measured and standardized. The current formulations available to the public in the health-food marketplace have the following dosages of withanolides: 1.5%; 2.5%; 4.5%; 8%.

Side Effects of Withania Somnifera

• Ashwagandha is not toxic at normal doses (up to 2g per day for up to 3 months);
• At high dosages (5g per day for 30 days) some toxicity is noted (spleen, thymus, adrenal glands); longer term use (180 days) at high dosage also results in some toxicity (heart and adrenals);
• ashwagandha has some abortifacient effects; avoid use if pregnant or lactating.

Quotations from Recent Research Abstracts

Abstract 1 (2005): Withanolide plus Withanoside and Reconstruction of Neuronal Networks.
"The reconstruction of neuronal networks in the damaged brain is necessary for the therapeutic treatment of neurodegenerative diseases. We have screened the neurite outgrowth activity of herbal drugs, and identified several active constituents. In each compound, neurite outgrowth activity was investigated under amyloid-beta-induced neuritic atrophy. Most of the compounds with neurite regenerative activity also demonstrated memory improvement activity in Alzheimer's disease-model mice. ... Withanolide derivatives (withanolide A, withanoside IV, and withanoside VI) isolated from the Indian herbal drug Ashwagandha, also showed neurite extension in normal and damaged cortical neurons. ..."

Title: Search for natural products related to regeneration of the neuronal network. Neurosignals. 2005;14(1-2):34-45;
Author: Tohda C, Kuboyama T, Komatsu K. Research Center for Ethnomedicines, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Japan.

Abstract 2 (April 2005): Withanolide and Neuritic Regeneration and Synaptic Reconstruction.
"We investigated whether withanolide A (WL-A), isolated from the Indian herbal drug Ashwagandha (root of Withania somnifera), could regenerate neurites and reconstruct synapses in severely damaged neurons. We also investigated the effect of WL-A on memory-deficient mice showing neuronal atrophy and synaptic loss in the brain. ... Subsequent treatment with WL-A ... induced significant regeneration of both axons and dendrites, in addition to the reconstruction of pre- and postsynapses in the neurons. WL-A ... recovered A beta(25-35)-induced memory deficit in mice. At that time, the decline of axons, dendrites, and synapses in the cerebral cortex and hippocampus was almost recovered. WL-A is therefore an important candidate for the therapeutic treatment of neurodegenerative diseases, as it is able to reconstruct neuronal networks."

Title: Neuritic regeneration and synaptic reconstruction induced by withanolide A. Br J Pharmacol. 2005 Apr;144(7):961-71.
Author: Kuboyama T, Tohda C, Komatsu K. Research Center for Ethnomedicines, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.

Abstract 3 (Oct 2002): Withanolides and Axon- and Dendrite- Outgrowth.
"We previously reported that the methanol extract of Ashwagandha (roots of Dunal) induced dendrite extension in a human neuroblastoma cell line. In this study, we found that six of the 18 compounds isolated from the methanol extract enhanced neurite outgrowth in human neuroblastoma SH-SY5Y cells. ... In withanolide A-treated cells, the length of NF-H-positive processes was significantly increased compared with vehicle-treated cells, whereas, the length of MAP2-positive processes was increased by withanosides IV and VI. These results suggest that axons are predominantly extended by withanolide A, and dendrites by withanosides IV and VI."

Title: Axon- or dendrite-predominant outgrowth induced by constituents from Ashwagandha. Neuroreport. 2002 Oct 7;13(14):1715-20.
Author: Kuboyama T, Tohda C, Zhao J, Nakamura N, Hattori M, Komatsu K. Research Center for Ethnomedicines, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan.

Abstract 4 (June 2002): Withanolides and Neurite Outgrowth.
"Five new withanolide derivatives (1, 9-12) were isolated from the roots of Withania somnifera together with fourteen known compounds (2-8, 13-19). On the basis of spectroscopic and physiochemical evidence, compounds 1 and 9-12 were determined to be ... . Of the isolated compounds, 1, withanolide A (2), (20S,22R)-4 beta,5 beta,6 alpha,27-tetrahydroxy-1-oxowitha-2,24-dienolide (6), withanoside IV (14), withanoside VI (15) and coagulin Q (16) showed significant neurite outgrowth activity at a concentration of 1 microM on a human neuroblastoma SH-SY5Y cell line."

Title: Withanolide derivatives from the roots of Withania somnifera and their neurite outgrowth activities. Chem Pharm Bull (Tokyo). 2002 Jun;50(6):760-5.
Author: Zhao J, Nakamura N, Hattori M, Kuboyama T, Tohda C, Komatsu K. Department of Metabolic Engineering, Toyama Medical and Pharmaceutical University, Sugitani, Japan.