The clinical efficacy of salvia officinalis An evaluation of the clinical efficacy of Salvia officinalis, Salvia lavandulaefolia and Melissa officinalis for the prophylaxis, management and amelioration of cognitive dysfunction: with particular reference to Alzheimers disease and non-Alzheimer-type senile dementias. 1. Introduction Dementia is a collection of symptoms caused by a chronic, global deterioration of cognitive function. It can occur at any age but is most prevalent in the elderly and increases with age (Beers et al. 2006: 1811). Around 5% of people over 65, 25% over 80 and 45% over 85 have some form of dementia (Knapp et al. 2007: 10; Collins 1997: 185). The population is aging and whereas today there is an estimated 700,000 people in the UK suffering from dementia, this number is set to increase to more than a million by 2025. The huge impact dementia has on society, devastating families and costing around Â£17-18 million annually cannot be overstated (Knapp et al. 11). Early identification and safe, effective, intervention is therefore important. Dementia may be classified as Alzheimers or non-Alzheimer-types (Beers et al. 2006: 1811). The most common dementia is Alzheimers disease (AD) (Grossman et al. 2006: 985), affecting around 20 million people worldwide (Akhondzadeh et al. 2003: 53) and accounting for around 62% of dementias (Knapp et al. 2007: 11). Non-Alzheimer-type dementias typically affecting those over 60 include vascular dementia (27%), Lewy body dementia and fronto-temporal dementia (Knapp et al. 29). Cognitive disorders are treated allopathically with drugs that have yet to show real benefits and have a number of side-effects and contraindications. The need for safer, more effective treatments has led to increasing interest in the use of herbs for their management (Akhondzadeh and Abbasi 2006: 117). A variety of herbs, for example Salvia officinalis, Rosmarinus officinalis, Mellissa officinalis, Ginkgo biloba (Heinrich et al 2004: 234), Withania somnifera (Howes et al. 2003: 12), Centella asiatica (Chevallier 1996: 78) and Panax ginseng (Mantle et al. 2000: 207) have long-standing traditional use as memory-enhancing herbs. Consequently a number of clinical studies have been conducted to assess the efficacy of some of these herbs, most notably Ginkgo biloba, Salvia spp. and Mellissa officinalis, in the treatment of cognitive disorders. Of these, only clinical trials of Gingko biloba have been extensively reviewed (Birks and Grimley Evans 2002; Ernst et al. 1999; Oken et al. 1998). This present review aims to fill this gap by providing up-to-date information on whether clinical studies of Salvia spp. and Mellissa officinalis support their traditional use as cognition enhancers. To inform herbal practice it will evaluate clinical studies to assess whether the results have determined safe, effective herbal strategies and prescription for prophylaxis, management and amelioration of cognitive decline. 2. The literature review 2.1. Background: clinical presentation and pathology Although much scientific progress has been made since 1907 when Alois Alzheimer first described a case of dementia with â€œpeculiar patchesâ€ disseminated throughout the cerebral cortex (Collins 1997: 185), there is still much to learn about the aetiology and pathogenesis of Alzheimers disease and other dementias (Knapp et al. 2007: 11). The onset of dementia is insidious, often beginning as mild cognitive impairment (MCI) and progressing to severe dementia over time (Loveman et al. 2006: 4). In the early stages, episodes of mild forgetfulness or misplacing possessions are often attributed to normal aging. Patients commonly suffer from anomic aplasia and agnosia but retain language comprehension (Collins 1997: 186). Dementia becomes more apparent when sufferers are unable to learn new information, to register the content of a conversation, or to recall recent events or the names of family members. Unlike those with benign forgetfulness, dementia patients are unaware of their amnesia. Frequently, there are mood changes, depression and other psychologic disturbances. Language comprehension fails (aphasia) and eventually patients may simply repeat what they hear or be unable to speak at all. Visuospacial deficits usually occur at a late stage (Collins 1997: 186). Those affected have difficulty in copy drawing simple objects. Differential diagnosis between MCI subtypes of various and complex aetiologies is challenging (Kidd 1999: 145). As some MCI subtypes are reversible (Levey et al. 2006: 992) prophylaxis for dementia could potentially encompass a range of varied or unknown aetiologies and risk factors. Knowledge of these and an awareness of differing clinical presentations are therefore important (Levey et al: 991). Additionally, an understanding of current orthodox treatment strategies and key neurochemical impairments in dementia can inform herbal practice of the most likely therapeutic actions of herbs. 2.1.1. Alzheimers disease As clinical studies have indicated that mild to moderate Alzheimers disease (AD) responds better to allopathic drugs than severe AD (Levey et al: 2006: 993), to prevent transition of MCI to AD early diagnosis is important. Evidence suggests that MCI associated with memory loss most commonly leads to AD (Levey et al. 991) and results of a clinicopathologic study of 80 subjects with MCI through to autopsy suggest that depression is one of the first features of AD (Galvin et al. 2005: 763). Formation of diffuse neuritic senile plaques in the brain is characteristic of AD but as these can only be determined from biopsy (Collins 1997: 186) probable diagnosis is made by clinical neuropsychological testing (Grossman et al. 2006: 986) such as the Mini Mental state Examination (MMSE) (Alzheimers Society 2002: 436), while magnetic resonance imaging can corroborate diagnosis by identifying areas of temporal neuronal loss (Vandenberghe and Tournay 2004: 347). Progression of AD is unremitting for around 5-10 years until death ensues. In the final stages sufferers may develop apraxia, with difficulty in performing familiar tasks. A common cause of death is pneumonia when patients eventual difficulty with eating results in aspiration pneumonia (Collins 1997: 186). The loss of faculties has been ascribed to both structural and neurochemical abnormalities (Perry et al. 1996: 1063). Senile plaques in the brains of AD patients contain amyloid and tau protein (microtubule associated protein) (Collins 1997: 188). Since isolation of b-amyloid peptide from cerebral vessels in AD patients (Wong et al. 1984: 8729), the accepted hypothesis for the pathogenesis of AD has been the â€˜amyloid hypothesis, which proposes that AD is due to excessive formation of extracellular b-amyloid (Ab?) from amyloid precursor protein (APP), a membrane protein in neurons (Grossman et al. 2006: 986). It is thought that Ab molecules initiate a toxic cascade long before plaque forms by causing an inflammatory reaction, disrupting synaptic function and causing neurons to degenerate (Grossman et al. 986) with a loss of cholinergic fibres in the basal forebrain. In vitro results suggest that Ab enters mitochondria and induces free radical damage (Reddy 2006: 9). Intracellular neurofibrillary tangles are believed to be formed by abnormal phosphorylation of tau proteins (Tanzi and Bertram 2005: 545), particularly in the hippocampus and neocortex, areas of the brain involved in memory (Mantle et al. 2000: 202). To date, thirteen genes have been implicated in AD (Bertram et al. 2007: 17). Of sporadic late onset Alzheimers up to 40% of cases may be due to a faulty gene on chromosome 21, ApoE4, an isoform of the ApoE gene that encodes for apolipoprotein, an astrocytic protein that may play a role in the reparative process in the brain. ApoE4s pathogenetic mechanism may be to enhance amyloid deposits within tissue by accelerating cleavage of b-peptide (Collins 1997: 189). Possession of a gene implicated in AD does not necessarily result in its development, the likelihood of which is further complicated by the potential role of environmental factors such as viruses and toxins in combination with genetic factors (Bird 2005: 864). 2.1.2. Vascular dementia Vascular dementia (VaD) is any type of dementia caused by cerebral blood vessel disease (Micieli 2006: S37). Onset of VaD is usually abrupt. Imaging may reveal areas of multiple infarcts (Collins 1997: 191) but their presence does not necessarily imply dementia (Grossman 2006: 987). According to Looi and Sachdev (1999) it is not possible to differentiate between AD and VaD with neuropsychological testing. Speech and language difficulties associated with vascular dementia may be mild or there may be a more pronounced aphasia as in multi-infarct VaD (Collins 1997: 191). 2.1.3. Frontal lobe dementia Frontal lobe dementia or Picks disease is uncommon and is characterised by neuronal loss and gliosis. Rarely, there are fibrillary inclusion bodies in the neurons. Presentation of frontal lobe dementia differs from AD in that the first symptoms are a change in personality rather than memory loss (Collins 1997: 193). 2.1.4. Lewy body dementias Dementia with Lewy bodies may differ to AD in its presentation in that patients suffer from marked visual hallucinations. Additionally, cognition tends to fluctuate between normality and confusion. Parkinsonian features such as shuffling gait, tremor, bradykinesia and rigidity are prevalent. Sleep behaviour disorder, such as acting out attacking themes, may appear years before other signs of the disease (Grossman et al. 2006: 989). 2.2. Risk factors Factors believed to pose a risk for developing dementia include cardiovascular disease, being female, a family history of dementia, Downs syndrome, older age, head trauma, diabetes and lower educational standards (Collins 1997: 186, 188; Lebson et al. 1997: 301). 2.2.1. Cardiovascular disease: Patients may have more than one type of dementia concurrently (Beers et al. 2006: 1811). This is compounded by results of a number of epidemiological studies suggesting that cardiovascular disease increases the risk of developing AD (Stampfer 2006: 12). Using transcranial Doppler ultrasonography Sun et al. (2007: 152) demonstrated diminished cerebral blood flow velocities in MCI patients who also carried the ApoeE4 allele. Risk factors for VaD are believed to include artherogenic factors such as hypertension, hyperlipidaemia, diabetes, and cigarette smoking (Micieli 2006: S38). Conversely, there are indications from clinical trials that nicotine has a protective effect for AD (Breteler et al. 1992: 71). Results of a randomised, double-blind, multicentred trial in which subjects with hypertension were treated with antihypertensives or placebo suggest that hypertension is a risk factor for developing both AD and VaD. Antihypertensives reduced risk by 55%. The results were significant as subjects had similar characteristics, the sample size was large (3228) and equally divided into placebo and treatment groups. Median follow-up was 3.9 years (Forette et al. 2002: 2047). 2.2.2. Head trauma: A meta-analysis by Fleminger et al. (2003: 858) replicated earlier findings by Mortimer et al. (1991) that head injuries pose a risk for AD but only in males, thought to be due to an early protective effect of oestrogens in females (Fleminger et al. 860). Bias may have been introduced into both studies as informants recalled the injuries. 2.2.3. Diabetes mellitus: Given that diabetes mellitus (DM) is a known risk factor for vascular disease it is not surprising that most studies on the development of vascular dementia in DM patients have shown a positive association (Biessels 2004: 10). Studies on DM as a risk factor for AD, however, have yielded conflicting results, possibly due to study limitations such as small sample sizes and selection bias (Leibson et al. 1997: 301). Large longitudinal studies may be more reliable. A population-based historical cohort study of 1,455 cases followed over 9,981 person years found a statistically significant positive association (Leibson et al. 304). According to results from the Framlingham Study, diabetes may not be an independent risk factor for developing AD but risk is strongly associated with possession of the ApoE4 genotype (Akomlafe et al. 2006: 1551). 2.2.4. Hormones: Women are twice more likely than men to suffer from AD. Although this may be partly due to women having a longer life expectancy (Beers et al. 2006: 1814) there is evidence to suggest that a decline in endogenous oestrogen in later life plays a role in its pathogenesis. Oestrogen is believed to stimulate cholinergic activity, reduce oxidative stress related cell damage, reduce vascular risks, reduce Ab formation and promote synaptic activity (Zandi et al. 2002: 2123; Hoskin et al. 2004: 141). Evidence from studies to determine whether oestrogen-containing hormone replacement therapy (HRT) in women has a protective effect on the brain, however, is conflicting (Colucci et al. 2006: 1376) but this may be due to differences in methodology and confounding factors (Resnick and Henderson 2002: 2171). For example, in one large prospective study that found a positive correlation between HRT use and a significant reduction in AD development, patients with dementia were asked questions regarding previous use of HRT (Zandi et al. 2124) yet accurate recall in a dementia sufferer cannot be guaranteed. Results of a retrospective case-control study suggesting the likelihood of women developing AD increases with number of pregnancies (Colucci et al. 2006: 1375) could be of little value. Cases with previous head injuries, low educational standards, both considered risk factors for AD (Collins 1997: 186; Fleminger et al. 2003: 858), and those who had used HRT, were not excluded from the study. There is evidence to suggest testosterone may delay AD onset in men. Men over 32 years of age who were free from AD at baseline (n = 574) were followed for a mean of nineteen years (Moffat et al. 2004: 188). Long-term free testosterone levels were significantly lower in men who developed AD. Due to conflicting results and confounding factors in the research the clinical evidence for risk factors for dementia is inconclusive. However, although more research is needed the results can assist in informing herbal practice. 2.3. Orthodox treatment strategies As cholinergic neurotransmitters are believed to have a role in memory function (Grossman et al. 2006: 985) symptomatic treatment for subtypes of dementia is similar and focuses on acetylcholinesterase (AChE) inhibition with drugs such as donepezil, rivastigmine and galantamine (Loveman et al. 2006: 8). According to Delagarza (2003: 1366) loss of cholinergic neurons causes a decrease in acetylcholine and subsequent drop in AChE with a compensatory rise in butylcholinesterase (BChE). Nicotinic receptors also decrease. Rivastigmine also inhibits BChE; galantamine also acts on nicotinic receptors. Depression in dementia is treated with non-anticholinergic antidepressants as anticholinergic drugs exacerbate symptoms (Beers et al. 2006: 1814). Another drug, memantine, a N-methyl-D-aspartic acid (NMDA) receptor antagonist (Grossman et al. 987), licensed to treat moderate to severe AD, acts by modulating the action of the neurotransmitter glutamate, which is believed to be associated with cholinergic damage and neurodegeneration when secreted in excess (Loveman et al. 2006: 8). Dizziness, diarrhoea, headaches, nausea and vomiting were found by a meta-analysis of dementia drugs to be common adverse events with anti-cholinesterases and memantine (Loveman et al. 2006: 49). Furthermore, their long-term benefits are inconclusive (Loveman et al. 145). Similarly, their use for vascular or Lewy body dementia is controversial as a review of clinical trials data deems there is insufficient evidence for their efficacy. Trials were of generally poor quality and with inconsistent findings (Maggini et al. 2006: 457). Other potential drugs for AD include 70 new compounds formulated to interfere with the toxic amyloid cascade or to target inflammation, oxidation or apoptosis (Grossman et al 2006: 987). As g-aminobutyric acid (GABA) agonists can impair memory GABA antagonists are also being developed (Association of the British Pharmaceutical Industry). 2.4. Potential herbal treatment strategies In view of the hypothesised pathological sequelae, risk factors and current orthodox treatment of dementias, efficacious herbs for these conditions could potentially have one or more of AChE-inhibiting or cholinergic, antidepressant, hypotensive, hypoglycaemic, antioxidant, anti-inflammatory, GABA modulator, nicotinic agonist, testosterogenic and oestrogenic actions. According to Kennedy and Scholey (2006: 4614) orthodox AChE inhibitors are not well tolerated by patients as they are toxic alkaloids and European plants traditionally used for cognitive enhancement may therefore provide non-alkaloid safer alternatives. To this end Salvia officinalis, Salvia lavandulaefolia and Melissa officinalis, members of the Labiatae family (Lamiaceae), have been extensively investigated in vitro. 2.4.1. Salvia spp. Salvia is the largest genus in the Labiatae family with over 700 species. The most common European species are Salvia officinalis L (garden or common sage) (Figure 1) and Salvia lavandulaefolia Vahl (Spanish sage), both of which originate on the shores of the Mediterranean (Kennedy and Scholey 2006: 4614). S. officinalis is an aromatic, evergreen shrub up to 75 cm in height with greyish-green oblong to lanceolate opposite leaves covered in a fine down. It has bluish-violet, two-lipped flowers arranged in whorls (Wildwood 1998: 202). S. lavandulaefolia has narrower leaves and a lower spreading habit (Sergei Savelevs Database). Sage was used in medieval Europe as a tisane for prolonging life and is a traditional spring tonic for strengthening weak constitutions (Lipp 1996: 63). According to Culpepper (1826: 147) â€˜Sage is of excellent use to help the memory, warming and quickening the senses and an old country remedy, which indicates its efficacy for inflammation: â€˜A sunburnt face is eased by washing with sage tea (Page 1978: 41). Other traditional uses are for headaches and migraine (Page: 34). The major active constituents of the leaves of both species are believed to be the volatile oils (1.0-2.8%), containing monoterpenes such as a-pinene, b-pinene, 1-8-cineole, camphor, geraniol and thujone (Kennedy and Scholey 2006: 4615). S. officinalis contains around 50% a- and b- thujone whereas only traces have been found in S. lavandulaefolia. As thujone, a terpenoid ketone, is potentially neurotoxic, S. lavandulaefolia may provide a safer alternative than S. officinalis to orthodox dementia drugs (Perry et al. 1999: 530). However, S. officinalis is toxic only at doses of over 15 g (Grainger-Bissett and Wichtl 2001: 441) but the oil should not be ingested. Both species contain polyphenolic compounds including rosmarinic acid, methyl carnosate, luteolin, luteolin-7-0-glucoside and caffeic acid (Kennedy and Scholey 4615), triterpenes eg oleanic acid and the flavonoids 5-Methoxysalvagenin (Barnes et al. 2002: 408) and hispidulin (Johnston and Beart 2004: 809). 2.4.2. Melissa officinalis M. officinalis L (balm, lemon balm) (Figure 2) originates from the eastern Mediterranean region and western Asia and is now widely cultivated in the west (Grainger Bissett and Wichtl 2001: 329). It is a bushy perennial, about 60 cm high with bright green, lemon-scented leaves in opposite pairs. Small labiate flowers grow in whorls and change colour from pale yellow to white or pale blue. Fresh leaves should be collected when young (Wildwood 1998: 175). It has been in medicinal use as a nervous system restorative for over 2000 years (Kennedy and Scholey 2006: 4617). The London Dispensary (1696 cited in Grieve 1931) states: â€˜An essence of Balm, given in Canary wine every morning will renew youth, strengthen the brain John Evelyn wrote: â€˜Balm is sovereign for the brain, strengthening the memory and powerfully chasing away melancholy (cited in Grieve 1931). There are no known contraindications or adverse effects (Barnes et al. 2002: 339). M. officinalis contains 0.2-0.3% essential oil (EO) consisting of over 70 components including around 60% monoterpenoid aldehydes and over 35% sesquiterpenes. The principle monoterpenes include citronellol, neral, geranial, methyl citronellate, ocimene; major sesquiterpenes include b-caryophylene and germacrene D. The herb also contains flavonoids, caffeic and chlorogenic glycosides, polyphenolic acids such as rosmarinic acid, and triterpenes (Granger Bissett and Wichtl 2001: 330). 2.5. Possible mode of action of phytochemical constituents in dementia 2.5.1. Antioxidant properties Numerous studies have been conducted on Salvia officinalis in a search for natural antioxidants to use in the food industry. Consequently, results of chemical tests on purified extracts of the herb have suggested that phenolic compounds rosmarinic acid, carnosic acid, carnosol, carnosoic acid, rosmadiol, rosmanol, epirosmanol, isorosmanol, galdosol methyl carnosate, 9-erythrosmanol and luteolin-7-0-glucopyranoside have significant antioxidant activity (Bertelsen et al 1995: 1272; Cuvelier et al. 1994: 665; Pizzale et al. 2002: 1651; Miura et al. 2002: 1848; Wang et al. 1998: 4869). S. lavandulaefolia dried leaf extracts in ethanol, chloroform and water, and various EO monoterpenes were assayed for antioxidant properties in phospholipid microsomes. The extracts and monoterpenes a-pinene, b-pinene, 1-8-cineole, camphor and geraniol and thujone all showed significant antioxidant activity (Perry et al. 2001: 1351). The extracts showed greater antioxidant activity than any individual monoterpenes, which suggested a synergistic effect (Perry et al. 1352). Ferreira et al. (2006: 35) measured the antioxidant properties of EOs, decoctions and ethanolic extracts of M. officinalis and S. officinalis relative to b-carotene. The EO and decoctions of both herbs showed significant antioxidant activity. Lima et al (2007) found methanolic and aqueous extracts of S. officinalis prevented lipid peroxidation in hepatoma cells. As there were more phenolics in the methanol extract it was thought there were other antioxidant compounds in the aqueous extract. Ethanolic EO extract from dried M. officinalis investigated for its ability to inhibit lipid peroxidation in vitro showed a dose-dependent (10-20 mg) 80-90% protection of linoleic acid from peroxyl radical attack. As no rosmarinic acid was detected in the EO the antioxidant action was attributed to squalene (Marongiu et al. 2004: 790). Considering there are potentially 70 constituents in the EO it is unlikely that this would have been the only active phytochemical but composition of the oil varies according to harvesting, origin and climate (Grainger-Bissett and Wichtl 2001: 329). Interestingly, M. officinalis prepared as a tea demonstrated significant antioxidant capacity, which corresponded to high phenolic content, when assayed with the ABTS (2,2/-azinobis 3-ethylbenzothiazoline-6-sulfonic acid) radical decolourisation assay (Ivanova et al. 2005: 147). 2.5.2. Anti-inflammatory activity Chloroform, aqueous and ethanol extracts and monoterpenes of S. lavandulaefolia, were tested for their ability to inhibit formation of pro-inflammatory eicosanoids thromboxane B2 (TXB2) and leukotriene B4 (LTB4) in leucocytes (Perry et al. 2001: 1348). The chloroform and ethanol extracts showed significant inhibition of LTB4. Alpha-pinene and geraniol showed weak selectivity for LTB4 and TXB2 respectively (Perry et al. 1351). The results support the traditional use of S. lavandulaefolia as an anti-inflammatory herb but indicate that it is the sum of the whole plant phytochemicals acting in synergy that are likely to contribute to this action. A standardised ethanolic extract containing 9.9% rosmarinic acid (RA) from the leaves of S. officinalis reduced Ab-induced neuronal cell death, Ab-induced lipid peroxidation, reactive oxygen species formation, DNA fragmentation and tau protein hyperphosphorylation in vitro (Iuvone et al. 2006: 1143). Kimura et al (1987) found rosmarinic acid (RA) had the ability to inhibit pro-inflammatory cytokines in human polymorphonuclear leucocytes (PMNs) in vitro. As both species contain RA these results suggest antioxidant, anti-inflammatory and neuroprotective properties of M. officinalis and the Salvia spp. against Ab-induced neurotoxicity. 2.5.3. Oestrogenic activity A range of concentrations of EO, ethanolic, chloroform and aqueous extracts and isolated monoterpenes of S. lavandulaefolia were assayed in yeast culture for oestrogen-binding properties. The EO showed weak oestrogenic activity at low concentrations. The aqueous and ethanolic fractions and geraniol showed significant oestrogenic activity (Perry et al. 2001: 1352). The results of this experiment support S. lavandulaefolias use as an oestrogenic herb. The effects of S. officinalis in combination with Medicago sativa were assessed on menopausal symptoms related to oestrogen deprivation. Hot flushes and night sweats were completely eliminated in 20 out of 30 women (De Leo et al. 1998: 207). These effects were attributed to dopaminergic actions but it is not clear for which herb. S. officinalis does, however, contain geraniol found to be oestrogenic in vitro (Perry et al. 2001: 1352). 2.5.4. Acetylcholinesterase inhibitory activity M. officinalis EO demonstrated strong AChE inhibition in homogenised human brain tissue but ethanolic extract of the dried leaf had no effect. Ethanolic fresh leaf extract showed a weak effect (Perry et al. 1996: 1064). Conversely, when EOs and ethanolic extracts of M. officinalis were assayed in solution with AChE negligible results were obtained for its inhibition by EO and significant results for its ethanolic extract (Ferreira et al. 2006: 34). Dried, reconstituted ethanolic, ethyl acetate or aqueous extracts of M. officinalis, yielding 10mg/ml, demonstrated weak AChE inhibitory activity when assayed in a chemical system using thin layer chromatography (Salah and JÃ¤ger 2005: 146). The herbs were purchased from local suppliers in the Lebanon so their quality is unknown. S. officinalis EO and ethanolic extract assayed in solution with AChE showed moderate AChE inhibitory activity (Ferreira et al. 2006: 34). Moderate (dose-dependent) AChE and weak BChE inhibition was demonstrated by ethanolic extracts of fresh and dried S. officinalis and S. lavandulaefolia in human brain homogenates. The EOs had significant effects but not the individual constituents (camphor, thujone, cineole, caffeic acid and borneol) (Perry et al. 1996: 1066). The findings suggest a major synergistic effect of the constituents (Perry et al. 2000: 895), which was later confirmed by Savelev et al. (2003: 667). The results for camphor conflict with another experiment in which S. lavandulaefolia EO and isolated monoterpenes a-pinene, 1-8-cineole and camphor demonstrated AChE inhibitory activity in human erythrocytes. Ethanolic extracts of dried S. officinalis, S. lavandulaefolia and M. officinalis were assayed for acetylcholine (ACh) receptor activity in human brain homogenate. All plants demonstrated ACh receptor activity and M. officinalis had the highest nicotinic displacement value (Wake et al. 2000: 108). 2.5.5. GABA modulation Methanol extract from S officinalis leaves revealed the flavonoids apigenin, hispidulin and cirsimaritin functioning as benzodiazepine receptor-active components (Kavvadias et al. 2003: 113), suggesting a potential calming effect for the herb, which may be relevant to AD. 2.6. Evaluation of in vitro studies According to the results all three herbs may have AChE inhibitory, anti-inflammatory and antioxidant properties, and S. lavandulaefolia and S. officinalis may have and oestrogenic properties (Appendix I, Table 1, page 36) and a sedative effect for S. officinalis. Although these results are interesting in vitro systems cannot be extrapolated to humans and clinical evidence is necessary to support findings. For example, they cannot determine effective human dosage or mode of administration. They largely do not account for potential synergistic effects of the herbs nor do they provide an indication of in vivo physiological, pathological and genetic, or environmental, influences. Furthermore, the extent to which phytochemicals in herbs are effective in dementia may depend upon their bioavailability in the brain (Anekonda and Reddy 2005: 371). It is worth noting, however, that as terpenoids tend to be lipophilic they are able to cross the blood brain barrier (Houghton and Howes 2005: 12). Some results are conflicting but they may depend on methodological quality and design. The experiments cited above vary widely in their approach with regard to extraction methods and assay methods. Savelev (2003: 667) has demonstrated how two different methods used for exploring interactions between the same agents may give different results when applied to the same set of data. Consistency of results may also be affected by differences in harvesting times and quality of herbs. Results for M. officinalis are particularly inconsistent but, according to Perry et al. (1996: 1068) most commercial sources of the EO are adulterated. Additionally, variation in media composition is known to affect the outcome of in vitro tests (Maurer and Kuschinsky 2006: 73). Consequently, in vitro experiments can only provide an indication of the clinical efficacy of therapeutic interventions. However, despite the inherent difficulties of in vitro research with herbs, there is considerable consistency with their potential value in dementia prophylaxis and management (Appendix I, Table I, page 36). Promising results in vitro of constituents of plants traditionally used to enhance memory, and subsequent interest in their potential actions in the brains of human patients, has generated clinical trials of M. officinalis and Salvia spp. for dementia. These will be reviewed. 3. Method A computerised literature search was conducted on the Allied and Complementary Medicine Database (AMED) including CINAHL Database, EMBASE, Pascal Biomed, Biological Abstracts, RCN Journals Database and IPA (International Pharmaceutical Abstracts); PubMed, the Cochrane Collaboration, Bandolier, the NHS Centre for Reviews, The National Research Register, ADEAR (Alzheimers Disease Education and Referral Centre database), PLoS (Public Library of Science), Herbalgram and Alt HealthWatch as well as hand-searching in books and journals. Literature searches dated back to 1985 and the final search was in April 2007. Key words in medical subject headings (MeSH) for an initial search in various Boolean combinations were: memory, cognitive dysfunction, dementia, Alzheimers, herbal, botanicals, phytotherapy, complementary and alternative. Also, in a second search these MeSh terms were entered with key herbs: Salvia, sage, Melissa and lemon balm. Inclusion criteria Controlled clinical trials, observational studies and case reports. Herbs for which there are at least two clinical studies in relation to cognitive enhancement. Exclusion criteria Due to the limitations and ethical considerations of animal experiments the review is restricted to human trials. Trials with combined preparations are excluded. Due to time constraints and a restriction to papers in the English language a complete systematic review is not viable at this time. To eliminate
Throughout the 20th century, the relations between the French and the English in Canada had a significant negative impact on Canadian history. The defining moments that changed French-English relations in Canada were the WWI conscription crisis, the creation and the governing of the Union Nationale Party in the 1930s, and Quebecâ€™s Quite Revolution in the 1960s.
The WWI conscription crisis considerably weakened the relations between the French and the English in Canada during WWI. By 1917, the casualty rates at the front in France and Flanders exceeded 109 4891 soldiers. As the number of volunteer soldiers was only about 64 3392 men, the lack of reinforcements forced Prime Minister Robert Borden to make conscription or compulsory military service a law for Canadians to ensure victory in war. However, many French Canadians opposed forcing men to enlist in the armed forces because they did not want to get involved in a European war and felt no obligation to defend France who had abandoned Quebec to defend its culture and language on its own in 1759. On the other hand, the English felt an obligation to defend Britain and could not comprehend why Quebec had only provided twenty percent3 of the volunteers in proportion to its population to defend France.
As a result, the social unity of the French and the English in the country was threatened. The vote for conscription was split fifty-fifty4 along linguistic lines and the tragic outcome of this crisis was that civil war almost broke out in Canada when the French rioted in Montreal against fighting a foreign war. The demonstrations and protests in Quebec against conscription and the mistrust of the English who felt that a vote against conscription was a vote for Germanyâ€™s victory proved that conscription was disastrous to French-English social relations because of national unity had been destroyed for only 45 0005 recruited soldiers. Similarly, the long-term effects of the WWI conscription crisis caused extensive damage to French-English unity and proved to be a disaster in politics for the Conservative Party.
Because Robert Borden and the Conservative Party passed laws such as the Military Voters Act and the War Time Elections Act to make conscription a law during WWI by giving votes to soldiers and women, the French turned against the Conservative Party because they saw them as the representatives of the English. These long-term political disasters that resulted from conscription crisis continued to demonstrate the weakenedÂ French and English relations to this day since Quebec had no Conservative Party premier for the past hundred and fifteen years.6 Because of the violent social conflicts such as riots and bitter political catastrophes such as the French mistrust of the Conservative Party, the WWI conscription crisis strained French-English relations and created bitter feelings that would affect the peacetime.
Another defining moment in Canadian history that greatly weakened French English relations was the creation and the government of the Union Nationale Party in Quebec in the 1930s. During the Great Depression, the agricultural industryâ€™s prices plummeted, forced over fifty percent7 of Quebecâ€™s population to migrate to cities and search for work. In 1936, Maurice Duplessis from the newly formed Union Nationale Party became Quebecâ€™s Premier and took seventy-two of the ninety seats8 in the government, with his promises to help French rural society and improve labor rights for the French factory workers who were struggling in the cities. However, during its time in power, the Duplessis government resisted change and encouraged the preservation of French values and traditions by adopting nationalistic policies and continuing to allow the English to dominate the majority of Quebecâ€™s business.
The Duplessis government ruled in an almost totalitarian manner to protect the French culture and managed to hold power of Quebec until 1959. They vigorously protected French values and beliefs during the Great Depression, but they failed to protect the French and English business relations that quickly weakened. They promises of the Union Nationale to provide protection for French workers with better labor laws such as higher minimum wages, workersâ€™ compensation, and pensions quickly raised English suspicion and mistrust toward the French because these capitalists owned and ran most of the corporations in Quebec. The fact that the Union Nationale saw the English corporations as exploiting the poor and wanted certain labor rights for French workers did not strengthen the economical relations between the English began to distrust the French as they saw them nationalizing and beginning to pose threats to their business profits.
In addiction to that, the English and French were further divided by the social conflicts caused by the governing policies of the Union Nationale. This occurred because the Union Nationale government encouraged the CatholicÂ Church to control education and other social programs in Quebec, obstructed to federal encroachment on provincial rights during WWI, and preserved traditional values and beliefs of the French such as the nobility of the plough to prevent them from being assimilated into the English culture.
This destabilized French English political, economical and predominantly social affairs in Canada because the French withdrew into a defensive shell and viewed any English intrusion and change to Quebec as harmful to the preservation of their culture. Therefore, the governing policies of the Union Nationale in the 1930s created greater French nationalism and the desire for separation from the rest of Canada to preserve their culture and weakened the relations between French and English Canadians by planting the seeds for another major conflict that would arrive suddenly and once again disrupt the nationâ€™s unity.
Indeed, the arrival of the next conflict that split the French and the English in Canada did arrive suddenly between 1950-66 and was marked as Quebecâ€™s Quite Revolution, which was disastrous for the nationâ€™s unity. When Maurice Duplessis of the Union Nationale Party died in 1959, Jean Lesage became Quebecâ€™s new Liberal Premier, winning fifty-one and a half percent9 of the popular vote. This ended Quebecâ€™s isolationist policy and started Maitres chez nous or Masters in our own house policy, which served as a strategic base for the upcoming changes in Quebec. The Quiet Revolution was a period of non-violent steady reform, modernization in Quebec, and the redefinition of the role of French Canadians who wanted equality with the English within Confederation.
However, the end of this peaceful movement came suddenly in 1966 with the creation of nationalist groups such as the Parti Revolution who adopted separatist ideologies and took control of the province of Quebec that was desperately seeking equality. Although the goal of the Quiet Revolution was to make French equivalent within the Confederation, its own ideology failed to strengthen the social and economical relations with the English Canadians. The new Liberal government refused to accept federal funding to modernize education, improve the labor code for French workers, and nationalize hydro-electric facilities in Quebec. As a result, the provincial taxes on individuals and corporations in Quebec became the third highest10 in Canada.
Consequently, bitter social andÂ economical conflicts occurred between the English federalists and Quebecâ€™s business owners who became infuriated with the French because they refused federal funding in order to achieve greater power and therefore equality within Confederation. Furthermore, even greater political and social conflicts between the French Canadians and English Canadians were result of Quebecâ€™s Quiet Revolution. These major arguments were initiated in 1964 when the Liberal Party forced the Federal government to grant Quebec the right to opt out of thirty11 of the countryâ€™s cost sharing programs with full compensation.
The English in Canada as well as the federal government were greatly angered since only the province of Quebec was given this special status and their political differences with the French widened because the French did not see their special status as privilege, but rather as a way to gain more control and improve their position within Canada. Therefore, Quebecâ€™s Quiet Revolution was a catastrophic failure for French-English unity in Canada as it caused conflicts between federalists and nationalists in Quebec and in the federal government and failed to make any two provinces equal within Confederation.
Throughout the twentieth century it was evident that the French and the English engaged in severe social, political, and economical conflicts that prevented Canada from merging as a country. The WWI conscription crisis in 1917 bitterly split the nation at a time when national unity was important to ensure victory in the war as it made the French feel like a minority and caused great mistrust of the English who viewed them as being unpatriotic to the country.
The government of the Union Nationale during the 1930s caused even stronger breakdowns to French-English relations as it build a defensive shell around Quebec and isolated the French from the rest of Canada in an attempt to protect their traditions. Subsequently, Quebecâ€™s Quit Revolution from 1960-66 failed to bring an end to these conflicts as it caused greater English mistrust and resulted in the formation of militant groups in Quebec who believed that only a violent revolution would finally allow them to achieve total independence and equality within Confederation.
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