Alzheimers 6 - Rosemary 1

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Screening of plants used in Danish folk medicine to treat memory dysfunction for acetylcholinesterase inhibitory activity

            (Adsersen, Gauguin et al. 2006) Download

Aqueous and methanolic extracts of 11 plants, used in Danish folk medicine for improvement of memory and cognition, and 3 Corydalis species were tested for acetylcholinesterase inhibitory activity using the Ellman colorimetric method. Significant inhibitory activity in dose-dependent manner was observed for extracts of Corydalis cava, Corydalis intermedia, Corydalis solida ssp. laxa and Corydalis solida ssp. slivenensis. Extracts of Ruta graveolens, Lavandula angustifolia, Rosmarinus officinalis, Petroselinum crispum and Mentha spicata exhibited moderate inhibition of the enzyme, defined as more than 15% at 0.1 mg/ml.

The psychopharmacology of European herbs with cognition-enhancing properties

            (Kennedy and Scholey 2006) Download

Extensive research suggests that a number of plant-derived chemicals and traditional Oriental herbal remedies possess cognition-enhancing properties. Widely used current treatments for dementia include extracts of Ginkgo biloba and several alkaloidal, and therefore toxic, plant-derived cholinergic agents. Several non-toxic, European herbal species have pan-cultural traditions as treatments for cognitive deficits, including those associated with ageing. To date they have not received research interest commensurate with their potential utility. Particularly promising candidate species include sage (Salvia lavandulaefolia/officinalis), Lemon balm (Melissa officinalis) and rosemary (Rosmarinus officinalis). In the case of sage, extracts possess anti-oxidant, estrogenic, and anti-inflammatory properties, and specifically inhibit butyryl- and acetyl-cholinesterase. Acute administration has also been found to reliably improve mnemonic performance in healthy young and elderly cohorts, whilst a chronic regime has been shown to attenuate cognitive declines in sufferers from Alzheimer's disease. In the case of Melissa officinalis, extracts have, most notably, been shown to bind directly to both nicotinic and muscarinic receptors in human brain tissue. This property has been shown to vary with extraction method and strain. Robust anxiolytic effects have also been demonstrated following acute administration to healthy humans, with mnemonic enhancement restricted to an extract with high cholinergic binding properties. Chronic regimes of aromatherapy and essential oil respectively have also been shown to reduce agitation and attenuate cognitive declines in sufferers from dementia. Given the side effect profile of prescribed cholinesterase inhibitors, and a current lack of a well tolerated nicotinic receptor agonist, these herbal treatments may well provide effective and well-tolerated treatments for dementia, either alone, in combination, or as an adjunct to conventional treatments.

Carnosol, a component of rosemary (Rosmarinus officinalis L.) protects nigral dopaminergic neuronal cells

            (Kim, Kim et al. 2006) Download

Carnosol, a major component of Rosmarinus officinalis, is a phenolic diterpene that has potent antioxidant and anti-inflammatory activities. In this study, we investigated the protective effects of carnosol on rotenone-induced neurotoxicity in cultured dopaminergic cells. Results showed that cell viability was significantly improved with carnosol through downregulation of caspase-3. Furthermore, carnosol significantly increased the tyrosine hydroxylase, Nurr1, and extracellular signal-regulated kinase 1/2. These results suggest that carnosol may have potential as a possible compound for the development of new agents to treat Parkinson's disease.

Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells

            (Kosaka, Mimura et al. 2010) Download

Neurotrophins such as NGF promote neuronal survival and differentiation via the cell surface TrkA neurotrophin receptor. Compounds with neurotrophic actions that are low in molecular weight and can permeate the blood-brain barrier are promising therapeutic agents against neurodegenerative diseases such as Alzheimer's disease. Carnosic acid (CA), an electrophilic compound in rosemary, activates antioxidant responsive element (ARE)-mediated transcription via activation of Nrf2. In the present study, we discovered that CA strongly promotes neurite outgrowth of PC12h cells. NGF as well as CA activated Nrf2, whereas CA and NGF-mediated neuronal differentiation was suppressed by Nrf2 knockdown. On the other hand, CA activated TrkA-downstream kinase Erk1/2 independently of Nrf2. CA-induced p62/ZIP expression in an Nrf2-dependent manner, while the CA-induced neural differentiation was suppressed by p62/ZIP knockdown. Furthermore, CA-induced ARE activation was attenuated both by p62/ZIP knockdown and a Trk signal inhibitor. These results suggest that the CA induction of p62/ZIP by Nrf2 enhances TrkA signaling which subsequently potentiates Nrf2 pathway. This is the first demonstration that activation of the Nrf2-p62/ZIP pathway by a low-molecular natural electrophilic compound plays important roles in TrkA-mediated neural differentiation and may represent the common molecular mechanism for neurotrophic activities of electrophilic compounds.

Beneficial effects of carnosic acid on dieldrin-induced dopaminergic neuronal cell death

            (Park, Kim et al. 2008) Download

Carnosic acid (CA) is one of the bioactive polyphenols present in extracts of the herb rosemary (Rosmarinus officinalis). In this study, we examined possible protective effects of CA on neurotoxicity induced by dieldrin, an organochlorine pesticide implicated in sporadic Parkinson's disease, in cultured dopaminergic cells (SN4741). CA (5-10 muM) pretreatment showed potent protective effects in a concentration-related manner and prevented dieldrin (10 muM)-induced caspase-3 activation, Jun N-terminal kinase phosphorylation, and caspase-12 activation. Furthermore, dieldrin-induced downregulation of brain-derived neurotrophic factor production was significantly attenuated by CA. These results suggest that CA may safeguard dopaminergic neuronal cells from environmental neurotoxins by enhancing brain-derived neurotrophic factor and repressing apoptotic molecules.

Short-Term Study on the Effects of Rosemary on Cognitive Function in an Elderly Population

            (Pengelly, Snow et al. 2011) Download

Abstract Rosemary (Rosmarinus officinalis L.) has traditional reputations that justify investigation for a potential role in reducing widespread cognitive decline in the elderly. A randomized, placebo-controlled, double-blinded, repeated-measures crossover study was conducted to investigate possible acute effects of dried rosemary leaf powder on cognitive performance. Twenty-eight older adults (mean age, 75 years) were tested using the Cognitive Drug Research computerized assessment system 1, 2.5, 4, and 6 hours following a placebo and four different doses of rosemary. Doses were counterbalanced, and there was a 7-day washout between visits. There was a biphasic dose-dependent effect in measures of speed of memory: the lowest dose (750 mg) of rosemary had a statistically significant beneficial effect compared with placebo (P=.01), whereas the highest dose (6,000 mg) had a significant impairing effect (P<.01). There were significant deleterious effects on other measures of cognitive performance, although these were less consistent. Speed of memory is a potentially useful predictor of cognitive function during aging. The positive effect of the dose nearest normal culinary consumption points to the value of further work on effects of low doses over the longer term.


Carnosic acid protects neuronal HT22 Cells through activation of the antioxidant-responsive element in free carboxylic acid- and catechol hydroxyl moieties-dependent manners

            (Satoh, Izumi et al. 2008) Download

In a previous study, we found that carnosic acid (CA) protected cortical neurons by activating the Keap1/Nrf2 pathway, which activation was initiated by S-alkylation of the critical cysteine thiol of the Keap1 protein by the "electrophilic"quinone-type of CA [T. Satoh, K. Kosaka, K. Itoh, A. Kobayashi, M. Yamamoto, Y. Shimojo, C. Kitajima, J. Cui, J. Kamins, S. Okamoto, T. Shirasawa, S.A. Lipton, Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1. J Neurochem., in press]. In the present study, we used HT22 cells, a neuronal cell line, to test CA derivatives that might be more suitable for in vivo use, as an electrophile like CA might react with other molecules prior to reaching its intended target. CA and carnosol protected the HT22 cells against oxidative glutamate toxicity. CA activated the transcriptional antioxidant-responsive element of phase-2 genes including hemeoxygenase-1, NADPH-dependent quinone oxidoreductase, and gamma-glutamyl cysteine ligase, all of which provide neuroprotection by regulating cellular redox. This finding was confirmed by the result that CA significantly increased the level of glutathione. We synthesized a series of its analogues in which CA was esterified at its catechol hydroxyl moieties to prevent the oxidation from the catechol to quinone form or esterified at those moieties and its carbonic acid to stop the conversion from CA to carnosol. In both cases, the conversion and oxidation cannot occur until the alkyl groups are removed by an intracellular esterase. Thus, the most potent active form as the activator of the Keap1/Nrf2 pathway, the quinone-type CA, will be produced inside the cells. However, neither chemical modulation potentiated the neuroprotective effects, possibly because of increased lipophilicity. These results suggest that the neuroprotective effects of CA critically require both free carboxylic acid and catechol hydroxyl moieties. Thus, the hydrophilicity of CA might be a critical feature for its neuroprotective effects.

Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1

            (Satoh, Kosaka et al. 2008) Download

Electrophilic compounds are a newly recognized class of redox-active neuroprotective compounds with electron deficient, electrophilic carbon centers that react with specific cysteine residues on targeted proteins via thiol (S-)alkylation. Although plants produce a variety of physiologically active electrophilic compounds, the detailed mechanism of action of these compounds remains unknown. Catechol ring-containing compounds have attracted attention because they become electrophilic quinones upon oxidation, although they are not themselves electrophilic. In this study, we focused on the neuroprotective effects of one such compound, carnosic acid (CA), found in the herb rosemary obtained from Rosmarinus officinalis. We found that CA activates the Keap1/Nrf2 transcriptional pathway by binding to specific Keap1 cysteine residues, thus protecting neurons from oxidative stress and excitotoxicity. In cerebrocortical cultures, CA-biotin accumulates in non-neuronal cells at low concentrations and in neurons at higher concentrations. We present evidence that both the neuronal and non-neuronal distribution of CA may contribute to its neuroprotective effect. Furthermore, CA translocates into the brain, increases the level of reduced glutathione in vivo, and protects the brain against middle cerebral artery ischemia/reperfusion, suggesting that CA may represent a new type of neuroprotective electrophilic compound.


References

Adsersen, A., B. Gauguin, et al. (2006). "Screening of plants used in Danish folk medicine to treat memory dysfunction for acetylcholinesterase inhibitory activity." J Ethnopharmacol 104(3): 418-22.

Kennedy, D. O. and A. B. Scholey (2006). "The psychopharmacology of European herbs with cognition-enhancing properties." Curr Pharm Des 12(35): 4613-23.

Kim, S. J., J. S. Kim, et al. (2006). "Carnosol, a component of rosemary (Rosmarinus officinalis L.) protects nigral dopaminergic neuronal cells." Neuroreport 17(16): 1729-33.

Kosaka, K., J. Mimura, et al. (2010). "Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells." J Biochem 147(1): 73-81.

Park, J. A., S. Kim, et al. (2008). "Beneficial effects of carnosic acid on dieldrin-induced dopaminergic neuronal cell death." Neuroreport 19(13): 1301-4.

Pengelly, A., J. Snow, et al. (2011). "Short-Term Study on the Effects of Rosemary on Cognitive Function in an Elderly Population." J Med Food.

Satoh, T., M. Izumi, et al. (2008). "Carnosic acid protects neuronal HT22 Cells through activation of the antioxidant-responsive element in free carboxylic acid- and catechol hydroxyl moieties-dependent manners." Neurosci Lett 434(3): 260-5.

Satoh, T., K. Kosaka, et al. (2008). "Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1." J Neurochem 104(4): 1116-31.