Salvia miltiorhiza

The dried root of Salvia miltiorhiza Bunge (Lamiaceae), also known as Chinese sage or ‘dan shen’, is red in colour and was therefore believed to be a treatment for blood disorders in folk medicine. In TCM the root has been used as a remedy to stabilise the heart and calm the nerves and to treat circulatory disorders, insomnia and neurasthenia, and to alleviate inflammation. The Pharmacopoeia of the People’s Republic of China (2005) includes Salvia miltiorhiza root as a remedy for fidgets and insomnia, amongst other indications. Salvia miltiorhiza root extracts have been investigated for a wide range of activities in relation to effects on the cardiovascular system but also for effects on the CNS, and in cerebral ischemia in particular. Some of the biological activities associated with Salvia miltiorhiza could also be relevant to the modulation of cognitive function and may provide some explanation for the traditional uses of this plant in some neural disorders.

Salvia miltiorhiza extracts have been shown to modulate the action of some neuropeptides, although studies on this subject are relatively limited and the pharmacological activities reported often provide theoretical explanations for their clinical relevance in CNS disorders. Salvia miltiorhiza has been suggested to modify the actions of vasoactive intestinal peptide (vasoactive intestinal peptide), a neuropeptide distributed within the gastrointestinal tract and CNS, and somatostatin, a CNS neuropeptide that has been implicated in learning and memory; both neuropeptides are considered to play a role in changes involved in cerebral ischemia. Salvia miltiorhiza has also been suggested to influence the action of substance P, which is associated with neuronal damage following cerebral ischemia and which is decreased in the brains of Alzheimer’s disease patients. The compounds in Salvia miltiorhiza that protect against ischemic damage in the CNS appear to be the tanshinones, including tanshinone lib, which was effective in reducing stroke-induced brain damage.

Salvia miltiorhiza may modify ischemic damage to the CNS by antioxidant effects. Since the metabolism of free fatty acids from the breakdown of lipid membranes and the generation of oxygen free radicals occur in ischemia, further brain injury occurs and cognitive ability may be affected. Salvia miltiorhiza reduces lipid peroxidation and could therefore protect against these effects on the CNS during ischemia. The herbal mixture known as ‘Salvia compositus’, composed of Dalbergia odorifera T.C.Chen (Leguminosae) and Salvia miltiorhiza, is reported to modulate electrical activities of the cerebral cortex, to ameliorate cerebral oedema and to inhibit oxidation of lipids.

Several compounds isolated from Salvia miltiorhiza root have shown antioxidant effects, which may explain any protective effects this plant may have against ischemic damage, and could also be relevant in modifying the progression of some cognitive disorders. The antioxidant modes of action of compounds from Salvia miltiorhiza are well documented. Caffeic acid dimers, trimers and tetramers are some of the antioxidant compounds from the root of this plant and include rosmarinic acid and salvianolic acids A and B, with the latter two compounds also protecting against memory impairment induced by cerebral ischemia in rodents. Salvianolic acid B also protects against amyloid-induced neurotoxicity in vitro, which was associated with an antioxidant effect. A series of quinones from the root of Salvia miltiorhiza have shown antioxidant activity in vitro. The antioxidant potency of these compounds was rosmariquinone, dihydrotanshinone, miltirone 1 > dehydrorosmariquinone > cryptotanshinone (47) > tanshinone Ha, which suggested that the structural features important for the antioxidant activity were additional conjugated double bonds in the A ring, a dihydrofuran ring rather than a furan ring and an isopropyl substituent ortho to a quinone carbonyl rather than a dihydrofuran ring.

The anti-inflammatory effects of some Salvia miltiorhiza components could perhaps be exploited for use in cognitive disorders. Tanshinones from Salvia miltiorhiza root were anti-inflammatory in vivo and were active against 5-lipoxygenase in vitro, although they were not as active as the crude extracts, suggesting that other compounds from the root may be more potent against lipoxygenase activity, or perhaps a syner-gistic effect might occur with the crude extract. In addition to an anti-inflammatory action in vivo, tanshinone I inhibited phospholipase A2 and prostaglandin (prostaglandin) E2 formation in vitro, but did not affect COX-2 activity or expression, but cryptotanshinone does inhibit COX-2 activity. These studies suggest that cryptotanshinone, but not tanshinone I, may have potential in modulating inflammatory processes in cognitive disorders such as Alzheimer’s disease, since many studies suggest that cyclo-oxygenase-inhibiting drugs prevent or delay the onset of Alzheimer’s disease.

Other, perhaps more relevant, activities of Salvia miltiorhiza root are inhibition of neuronal cell death by inhibition of presynaptic glutamate release, currently a therapeutic target in Alzheimer’s disease, and protection against beta-amyloid-induced neuropathological changes in the hippocampus in vivo, effects observed with an extract and tanshinone, respectively. Also significant is that the first diterpenoids to show acetylcholinesterase inhibitory activity were isolated from Salvia miltiorhiza root, with dihydrotanshi-none and cryptotanshinone being the most active. These dihydrofurans were more active than the furans tanshinones I and Ha, suggesting that the more flexible dihydrofuran improves the binding affinity to the active site of the enzyme.

Although many activities associated with the treatment of cognitive disorders have been associated with numerous traditional remedies, studies to determine the bioavailability and if active compounds reach the site of action in the CNS are very limited. Studies on Salvia miltiorhiza compounds with regard to these parameters have shown that the bioavailability of salvianolic acid B and tanshinone Ha is low, and that penetration of cryptotanshinone across the blood-brain barrier may be limited in vivo, effects which may affect efficacy. In addition, an extract of Salvia miltiorhiza induced cytochrome P450, which raises the possibility of drug interactions, and treatment with a preparation of Salvia miltiorhiza in patients on long-term warfarin therapy increased haemorrhage risk.