A randomised double-blind placebo-controlled pilot trial of a combined extract of sage, rosemary and melissa, traditional herbal medicines, on the enhancement of memory in normal healthy subjects, including influence of age.

OBJECTIVE: To evaluate for the first time the effects of a combination of sage, rosemary and melissa (Salvia officinalis L., Rosmarinus officinalis L. and Melissa officinalis L.; SRM), traditional European medicines, on verbal recall in normal healthy subjects. To devise a suitable study design for assessing the clinical efficacy of traditional herbal medicines for memory and brain function. METHODS: Forty-four normal healthy subjects (mean age 61 ± 9.26y SD; m/f 6/38) participated in this study. A double-blind, randomised, placebo-controlled pilot study was performed with subjects randomised into an active and placebo group. The study consisted of a single 2-week term ethanol extract of SRM that was chemically-characterised using high resolution LC-UV-MS/MS analysis. Immediate and delayed word recall were used to assess memory after taking SRM or placebo (ethanol extract of Myrrhis odorata (L.) Scop.). In addition analysis was performed with subjects divided into younger and older subgroups (≤ 62 years mean age n = 26: SRM n = 10, Placebo n = 16; ≥ 63 years n = 19: SRM n = 13, Placebo n = 6). RESULTS: Overall there were no significant differences between treatment and placebo change from baseline for immediate or delayed word recall. However subgroup analysis showed significant improvements to delayed word recall in the under 63 year age group (p < 0.0123) with Cohen's effect size d = 0.92. No adverse effects were observed. CONCLUSION: This pilot study indicates that an oral preparation of SRM at the selected dose and for the period of administration is more effective than a placebo in supported verbal episodic memory in healthy subjects under 63 years of age. Short- and long- term supplementation with SRM extract merits more robust investigation as an adjunctive treatment for patients with Alzheimer's disease and in the general ageing population. The study design proved a simple cost effective trial protocol to test the efficacy of herbal medicines on verbal episodic memory, with future studies including broader cognitive assessment.

Increased neural progenitors in individuals with cerebral small vessel disease.

AIMS: Recent work has highlighted a significant increase of neural stem/progenitor cells after stroke in humans. In this study, we examined neurogenesis in small vessel disease, a key concurrent pathology in Alzheimer's disease. METHODS: We assayed autopsy tissue from 13 vascular dementia patients with small vessel disease and 12 age-matched subjects without cerebrovascular pathology, undertaking immunohistochemistry in the affected brain area and the subventricular zone with a well-characterized battery of antibodies to detect neural stem cells/progenitors and immature neurones, as well as choline acetyltransferase immunoreactivity. RESULTS: We showed significant increases ranging from 33% to 92% (P < 0.05) in neural progenitor cells around the areas of microvascular pathology and in the subventricular zone in patients with small vessel disease compared to individuals without cerebrovascular changes, even in patients with severe cerebrovascular disease, as defined by neuropathological assessment. Some of the progenitor cells give rise to immature neurones in the affected areas. These alterations were associated with vascular changes, but were unrelated to the cholinergic deficit observed in the cortex and subventricular zone in these patients, in contrast to other dementias examined such as dementia with Lewy bodies. CONCLUSIONS: This study provides evidence for neurogenesis in small vessel disease and may have important implications for the development of new therapies for neurodegenerative diseases.

Alterations in nicotinic α4ß2 receptor binding in vascular dementia using ¹²³I-5IA-85380 SPECT: comparison with regional cerebral blood flow.

OBJECTIVE: To investigate differences in distribution of α4ß2 subtypes of nicotinic acetylcholine receptors (nAChRs) using the ligand ¹²³I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) and single photon emission computed tomography (SPECT) in subjects with vascular dementia and age-matched controls. ¹²³I-5IA-85380 binding was compared to corresponding regional cerebral blood flow (rCBF) changes in the same subjects. METHODS: Thirty subjects (14 vascular dementia and 16 controls) underwent ¹²³I-5IA-85380 and rCBF ((99m)Tc-exametazime) SPECT scanning. Image analysis was performed on voxel basis using statistical parametric mapping (SPM2). RESULTS: Compared to controls, reductions in relative ¹²³I-5IA-85380 uptake were identified in dorsal thalamus and right caudate in vascular dementia. Increase in scaled ¹²³I-5IA-85380 uptake in cuneus was also demonstrated in vascular dementia relative to controls. Perfusion deficits in anterior cingulate were apparent in the patient group and did not appear to be associated with ¹²³I-5IA-85380 changes. CONCLUSIONS: Reduced ¹²³I-5IA-85380 uptake in vascular dementia was confined to sub-cortical regions, unlike the cortical reductions previously described in Alzheimer's disease. Elevation of normalised ¹²³I-5IA-85380 uptake in cuneus in vascular dementia could be a compensatory response to reduced cholinergic activity in dorsal thalamus.

Cholinesterase inhibitors reduce cortical Abeta in dementia with Lewy bodies.

Cholinesterase inhibitors (ChEIs) are effective symptomatic treatments in dementia with Lewy bodies (DLB), although effects on pathologic mechanisms are unknown. In the first human autopsy study examining the impact of ChEI treatment on brain pathology, we compared treated patients with DLB with matched untreated patients for cortical beta-amyloid (Abeta) and tau pathologies. Treated patients with DLB had significantly less parenchymal Abeta deposition, which is relevant to disease management and treatment of dementia patients using ChEI.

Alpha4beta2 nicotinic receptor status in Alzheimer's disease using 123I-5IA-85380 single-photon-emission computed tomography.

BACKGROUND: Loss of the alpha4beta2 nicotinic receptor subtype is found at autopsy in Alzheimer's disease. OBJECTIVE: To investigate in vivo changes in this receptor using single-photon-emission CT (SPECT) with 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380), a novel nicotinic acetylcholine receptor ligand which binds predominantly to the alpha4beta2 receptor. METHODS: 32 non-smoking subjects (16 with Alzheimer's disease and 16 normal elderly controls) underwent 123I-5IA-85380 and perfusion (99mTc-hexamethylenepropyleneamine oxime (HMPAO)) SPECT scanning. Region of interest analysis was performed with cerebellar normalisation. RESULTS: Significant bilateral reductions in nicotinic receptor binding were identified in frontal (left, p = 0.004; right, p = 0.002), striatal (left, p = 0.004; right, p = 0.003), right medial temporal (p = 0.04) and pons (p<0.001) in patients with AD compared to controls. There were no significant correlations with clinical or cognitive measures. The pattern of nicotinic binding significantly differed from that of perfusion in both patients with AD and controls. Both 123I-5IA-85380 and 99mTc-HMPAO SPECT imaging demonstrated similar diagnostic performance in correctly classifying controls and patients with AD. CONCLUSION: Using 123I-5IA-85380 SPECT we found changes consistent with significant reductions in the nicotinic alpha4beta2 receptor in cortical and striatal brain regions. This method could facilitate diagnosis and may be useful for monitoring progression of the disease and response to treatment in patients with AD and related diseases.

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Attenuation of Abeta deposition in the entorhinal cortex of normal elderly individuals associated with tobacco smoking.

Investigating correlates of tobacco smoking provides the only currently available opportunity of examining effects of long-term exposure of nicotinic receptors on a specific nicotinic agonist in human. Alzheimer-type pathology (Abeta and abnormally phosphorylated tau assessed on the basis of AT8 immunoreactivity) together with vascular markers has been compared in age-matched groups of normal elderly smokers and non-smokers in the entorhinal cortex, an area of noted age-related pathology. The density of total Abeta and diffuse Abeta immunoreactivity, together with formic acid-extractable Abeta42 but not Abeta40, was reduced in smokers (n = 10-18) compared with non-smokers (n = 10-20) (P < 0.05). There was also a reduced percentage of cortical and leptomeningeal vessels with associated Abeta immunoreactivity in smokers (n = 13) compared with non-smokers (n = 14) (P < 0.005 and 0.05, respectively). There was a significant inverse correlation between formic acid-extractable Abeta42 and pack years (n = 34, r = -0.389, P = 0.025), with a similar trend for total Abeta immunoreactivity which did not reach statistical significance (n = 30, r = -0.323, P = 0.082). In contrast, there were no significant group differences for vascular markers (collagen IV, alpha-actin or glucose transporter 1), AT8 immunoreactivity or phosphate-buffered saline-soluble Abeta peptides, and no significant associations with gender for any of the measured parameters. These findings are consistent with previously reported reductions in histologically assessed amyloid plaques in aged human brain associated with tobacco use and dramatic lessening of Abeta deposits in APPsw mice after nicotine treatment. Development of nicotinic drugs to protect against beta-amyloidosis as one of the principal pathological hallmarks of brain ageing and Alzheimer's disease is indicated.

Neuroleptics are associated with more severe tangle pathology in dementia with Lewy bodies.

BACKGROUND: Neuroleptics are only modestly effective in dementia and associated with a range of adverse effects including cognitive decline. Effects of the drugs on molecular pathology in brain tissue from people with dementia have not been investigated. OBJECTIVES: To compare the severity of Alzheimer type pathology in matched groups of people with dementia with Lewy bodies (DLB), treated and not treated with neuroleptics. METHODS: The relationship between neuroleptics and Alzheimer-type pathology was determined in 40 (17 neuroleptic treated, 23 neuroleptic free, matched for age, disease duration and psychosis) clinically prospectively studied, autopsy diagnosed DLB patients. RESULTS: In regression analyses, taking neuroleptics was significantly associated with increased neurofibrillary tangles but not amyloid plaques in cortical areas examined. The patient characteristics and the frequencies of key psychiatric symptoms were similar in the patients taking and not taking neuroleptics. CONCLUSION: Although patients were not randomized and the results which are observed need to be interpreted cautiously, if substantiated, this is an important finding with major implications for the pharmacological management of DLB patients and highlights the need to determine the impact of neuroleptics upon tangle pathology in AD.

Neuronal nicotinic acetylcholine receptor subunits in autism: an immunohistochemical investigation in the thalamus.

The cholinergic system has been implicated in the development of autism on the basis of neuronal nicotinic acetylcholine receptor (nAChR) losses in cerebral and cerebellar cortex. In the present study, the first to explore nAChRs in the thalamus in autism, alpha4, alpha7 and beta2 nAChR subunit expression in thalamic nuclei of adult individuals with autism (n=3) and age-matched control cases (n=3) was investigated using immunochemical methods. Loss of alpha7- and beta2- (but not alpha4-) immunoreactive neurons occurred in the paraventricular nucleus (PV) and nucleus reuniens in autism. Preliminary results indicated glutamic acid decarboxylase immunoreactivity occurred at a low level in PV, co-expressed with alpha7 in normal and autistic cases and was not reduced in autism. This suggested loss of neuronal alpha7 in autism is not caused by loss of GABAergic neurons. These findings indicate nicotinic abnormalities that occur in the thalamus in autism which may contribute to sensory or attentional deficits.

Positive modulation of mood and cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers.

Members of the Sage family, such as Salvia officinalis and Salvia lavandulaefolia, have a long history of use as memory-enhancing agents coupled with cholinergic properties that may potentially be relevant to the amelioration of the cognitive deficits associated with Alzheimer's disease. The current study utilised a placebo-controlled, double-blind, balanced, crossover design in order to comprehensively assess any mood and cognition modulation by S. lavandulaefolia. Twenty-four participants received single doses of placebo, 25 microl and 50 microl of a standardised essential oil of S. lavandulaefolia in an order dictated by a Latin square. Doses were separated by a 7-day washout period. Cognitive performance was assessed prior to the day's treatment and at 1, 2.5, 4 and 6 h thereafter using the Cognitive Drug Research (CDR) computerised test battery. Subjective mood ratings were measured using Bond-Lader visual analogue scales. The primary outcome measures were scores on the five cognitive factors that can be derived by factor analysis of the task outcomes from the CDR battery. The results showed that administration of S. lavandulaefolia resulted in a consistent improvement for both the 25- and 50-microl dose on the 'Speed of Memory' factor. There was also an improvement on the 'Secondary Memory' factor for the 25-microl dose. Mood was consistently enhanced, with increases in self-rated 'alertness', 'calmness' and 'contentedness' following the 50-microl dose and elevated 'calmness' following 25 microl. These results represent further evidence that Salvia is capable of acute modulation of mood and cognition in healthy young adults. The data also suggest that previous reports of memory enhancement by Salvia may be due to more efficient retrieval of target material.

Cholinergic nicotinic receptor involvement in movement disorders associated with Lewy body diseases. An autoradiography study using [(125)I]alpha-conotoxinMII in the striatum and thalamus.

The presence of alpha6 subunit containing nicotinic acetylcholine receptors on nigrostriatal dopaminergic neurons has been demonstrated in rodents and monkeys. [(125)I]alpha-conotoxinMII is a radioligand that binds to alpha6, and also alpha3 subunits of nicotinic acetylcholine receptors (nAChRs). In the present study, we have compared the distribution of [(125)I]alpha-conotoxinMII binding in post mortem human tissue from four groups of patients: individuals with dementia with Lewy bodies displaying extra-pyramidal features (DLB + EPF), DLB without extra-pyramidal features (DLB - EPF) Parkinson's disease without dementia (PD) and age-matched controls. Reduced binding was observed in the putamen and caudate in PD and both DLB groups. In DLB patients, the decline was greater in DLB + EPF compared to DLB - EPF group. The declines in nicotinic receptor binding in the striatum were in part paralleled by reductions in the striatal dopamine transporter. In the thalamus, [(125)I]alpha-conotoxinMII binding was significantly reduced in the centromedian nucleus in both DLB groups, and also in the parafascicular nucleus in the DLB - EPF group. In DLB + EPF and PD patients, there was decreased binding in the ventral lateral nucleus. This study demonstrates alterations of alpha6 and/or alpha3 nAChRs binding in DLB and PD, which are likely to relate to extra-pyramidal symptoms.

Cholinergic systems in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease characterized by akinetic-rigid features, falls, a supranuclear gaze palsy and subcortical dementia. Pathologically, there is abnormal accumulation of tau protein. Cholinergic deficits are thought to underlie the postural instability and cognitive impairment of PSP, but trials of cholinergic agonists and cholinesterase inhibitors have failed to show improvement in motor function, quality of life and cognitive impairment. The five cortico-basal ganglia loops, linking functionally related areas of the brain, are damaged in PSP, leading to specific clinical deficits. Cholinergic dysfunction is related to loss of cholinergic interneurons in the striatum, compounded by reduced inputs into the circuits from other cholinergic nuclei, such as the pedunculopontine nucleus and nucleus basalis of Meynert. Normal cholinergic transmission requires the presence of intact cholinergic neurons capable of releasing sufficient acetylcholine, and functional muscarinic and nicotinic receptors. Whilst there is evidence from autopsy and in vivo studies of loss of cholinergic neurons in PSP, the receptor status is unknown. This may be critical to understanding the basis for the poor therapeutic response to cholinomimetics. Symptomatic treatment using cholinergic drugs may thus be improved by more specific targeting of cholinergic receptors or nuclei. There is also evidence that cholinergic agents may have disease-modifying effects. This article reviews the key clinical features of PSP, along with normal basal ganglia anatomy and cholinergic transmission. Cholinergic deficits based on clinical and neurochemical parameters are then discussed, before concluding with suggested future directions for cholinergic treatments.

Selective changes in nicotinic acetylcholine receptor subtypes related to tobacco smoking: an immunohistochemical study.

Increases in neuronal nicotinic receptors (nAChRs) in response to nicotine exposure have been reported in cell cultures, rodent brains, and in the brains of human smokers. The present study examines alterations in alpha4 and alpha7 nAChR subunit cellular expression in human hippocampus and entorhinal cortex from normal elderly individuals with known smoking history. There were significant increases in the intensity of alpha4 immunoreactive neuropil, but not the number of cell bodies, in many regions of hippocampus and entorhinal cortex in smokers compared to age-matched non-smokers and ex-smokers. There was also an increase in alpha7 immunoreactive perikarya in the granular cell layer of dentate gyrus in smokers but not other regions examined. There was, in contrast, a significant reduction in alpha7 immunoreactive astrocytes in smokers and ex-smokers compared to non-smokers. These findings suggest exposure to tobacco smoke acutely up-regulates alpha4 receptors in axon terminals and dendrites but not perikarya, whereas tobacco smoking induced down-regulation of alpha7 expression on astrocytes is a long-term effect. As the alpha4 subunit decreases with ageing and degenerative diseases such as Alzheimer's disease, whereas alpha7 increases in astrocytes in Alzheimer's disease, the findings further indicate the therapeutic relevance of nicotinic agonists such as nicotine.

Molecular analysis of nicotinic receptor expression in autism.

Autism is a developmental disorder of unknown aetiopathology and lacking any specific pharmacological therapeutic intervention. Neurotransmitters such as serotonin, gamma-aminobutyric acid (GABA) and acetylcholine have been implicated. Abnormalities in nicotinic acetylcholine receptors have been identified including cortical loss of binding to the alpha4/beta2 subtype and increase in cerebellar alpha7 binding. Receptor expression (mRNA) has not so far been systematically examined. This study aims to further explore the role of nicotinic receptors in autism by analysing nicotinic receptor subunit mRNA in conjunction with protein levels and receptor binding in different brain areas. Quantitative RT-PCR for alpha4, alpha7 and beta2 subunit mRNA expression levels; alpha3, alpha4, alpha7 and beta2 subunit protein expression immunochemistry and specific radioligand receptor binding were performed in adult autism and control brain samples from cerebral cortex and cerebellum. Alpha4 and beta2 protein expression and receptor binding density as well as alpha4 mRNA levels were lower in parietal cortex in autism, while alpha7 did not change for any of these parameters. In cerebellum, alpha4 mRNA expression was increased, whereas subunit protein and receptor levels were decreased. Alpha7 receptor binding in cerebellum was increased alongside non-significant elevations in mRNA and protein expression levels. No significant changes were found for beta2 in cerebellum. The data obtained, using complementary measures of receptor expression, indicate that reduced gene expression of the alpha4beta2 nicotinic receptor in the cerebral cortex is a major feature of the neurochemical pathology of autism, whilst post-transcriptional abnormalities of both this and the alpha7 subtype are apparent in the cerebellum. The findings point to dendritic and/or synaptic nicotinic receptor abnormalities that may relate to disruptions in cerebral circuitry development.

Autism as a disorder of neural information processing: directions for research and targets for therapy.

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.

Nicotinic acetylcholine receptor distribution in Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and vascular dementia: in vitro binding study using 5-[(125)i]-a-85380.

Nicotinic acetylcholine receptors (nAChRs) have been implicated in a number of neurological disorders. 5-Iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a novel nAChR marker, binding predominantly to the alpha4beta2 subtype. This in vitro autoradiography study describes the distribution of 5-[(125)I]-A-85380 binding in post-mortem brain tissue from normal elderly individuals and from cases with age-associated dementias of both neurodegenerative and vascular types. The binding distribution of 5-[(125)I]-A-85380 in normal brain tissue was found to be consistent with the reported distribution of other high-affinity nicotinic ligands. In addition to high thalamic and moderate striatal and temporal cortex density, moderate 5-[(125)I]-A-85380 binding was also seen in white matter tracts in cingulate, occipital, and temporal areas, indicating the presence of nAChRs along nerve fiber tracts, which has not been reported in other high-affinity nicotinic agonist distribution studies. In Parkinson's disease (PD), loss of striatal 5-[(125)I]-A-85380 binding closely parallels the loss of nigrostriatal dopaminergic markers previously observed. In dementia with Lewy bodies (DLB) reduced striatal 5-[(125)I]-A-85380 binding density, comparable to that in PD, may be a marker of early degeneration in nigrostriatal inputs, while in Alzheimer's disease (AD) reduced striatal 5-[(125)I]-A-85380 binding could be related to reduced cortical inputs. The reductions of nAChRs seen in AD, DLB, and PD were not apparent in vascular dementia (VaD). In conclusion, 5-I-A-85380 is clearly a useful ligand for both in vitro and in vivo single photon emission tomography human studies investigating disease symptoms and progression, response to acetylcholinesterase-inhibiting drugs and in differentiating primary degenerative dementia from VaD.

Synergistic and antagonistic interactions of anticholinesterase terpenoids in Salvia lavandulaefolia essential oil.

In vitro anticholinesterase activities of eight commercially available terpenoid constituents of Salvia lavandulaefolia have been investigated. These included 1,8-cineole, camphor, alpha-pinene, beta-pinene, borneol, caryophyllene oxide, linalool and bornyl acetate. Dose-dependent inhibition of acetylcholinesterase (AChE) by these chemical constituents was determined using the method of Ellman [Biochem. Pharmacol. 7 (1961) 88]. The IC50 value of 1,8-cineole was 0.06+/-0.01 mg/ml similar to that of the essential oil (0.05+/-0.01 mg/ml). Analyses of the expected inhibitions based on the prediction of a zero interactive response of a combination at its naturally occurring ratios were carried out in comparison with observed inhibition. Minor synergy was apparent in 1,8-cineole/alpha-pinene and 1,8-cineole/caryophyllene oxide combinations, with interaction indexes not exceeding 0.5. In contrast, a combination of camphor and 1,8-cineole was antagonistic with an interaction index of 2. A combination of all eight compounds was zero interactive. A combination of six constituents, excluding 1,8-cineole and camphor, was used to compare the method of expected response of a combination with a method of summation. These findings reveal that the inhibitory activity of the oil results from a complex interaction between its constituents, which produce both synergistic and antagonistic responses between the component terpenes. Understanding such interactions is important in comparing species on the basis of chemical composition.

Salvia lavandulaefolia (Spanish sage) enhances memory in healthy young volunteers.

Sage (Salvia) has a longstanding reputation in British herbal encyclopaedias as an agent that enhances memory, although there is little evidence regarding the efficacy of sage from systematized trials. Based on known pharmacokinetic and binding properties, it was hypothesised that acute administration of sage would enhance memory in young adult volunteers. Two experiments utilised a placebo-controlled, double-blind, balanced, crossover methodology. In Trial 1, 20 participants received 50, 100 and 150 microl of a standardised essential oil extract of Salvia lavandulaefolia and placebo. In Trial 2, 24 participants received 25 and 50 microl of a standardised essential oil extract of S. lavandulaefolia and placebo. Doses were separated by a 7-day washout period with treatment order determined by Latin squares. Assessment was undertaken using the Cognitive Drug Research computerised test battery prior to treatment and 1, 2.5, 4 and 6 h thereafter. The primary outcome measures were immediate and delayed word recall. The 50 microl dose of Salvia essential oil significantly improved immediate word recall in both studies. These results represent the first systematic evidence that Salvia is capable of acute modulation of cognition in healthy young adults.

Modulation of mood and cognitive performance following acute administration of single doses of Melissa officinalis (Lemon balm) with human CNS nicotinic and muscarinic receptor-binding properties.

Melissa officinalis (Lemon balm) is a herbal medicine that has traditionally been attributed with memory-enhancing properties, but which is currently more widely used as a mild sedative and sleep aid. In a previous study it was demonstrated that a commercial Melissa extract led to dose-specific increases in calmness, and dose-dependent decrements in timed memory task performance. However, the extract utilized in that study did not exhibit in vitro cholinergic receptor-binding properties. The current study involved an initial screening of samples of M. officinalis for human acetylcholinesterase inhibition and cholinergic receptor-binding properties. The cognitive and mood effects of single doses of the most cholinergically active dried leaf were then assessed in a randomized, placebo-controlled, double-blind, balanced crossover study. Following the in vitro analysis, 20 healthy, young participants received single doses of 600, 1000, and 1600 mg of encapsulated dried leaf, or a matching placebo, at 7-day intervals. Cognitive performance and mood were assessed predose and at 1, 3, and 6 h postdose using the Cognitive Drug Research computerized assessment battery and Bond-Lader visual analog scales, respectively. In vitro analysis of the chosen extract established IC(50) concentrations of 0.18 and 3.47 mg ml(-1), respectively, for the displacement of [(3)H]-(N)-nicotine and [(3)H]-(N)-scopolamine from nicotinic and muscarinic receptors in the human cerebral cortex tissue. However, no cholinesterase inhibitory properties were detected. The most notable cognitive and mood effects were improved memory performance and increased 'calmness' at all postdose time points for the highest (1600 mg) dose. However, while the profile of results was overwhelmingly favorable for the highest dose, decrements in the speed of timed memory task performance and on a rapid visual information-processing task increased with decreasing dose. These results suggest that doses of Melissa officinalis at or above the maximum employed here can improve cognitive performance and mood and may therefore be a valuable adjunct in the treatment of Alzheimer's disease. The results also suggest that different preparations derived from the same plant species may exhibit different properties depending on the process used for the sample preparation.

Differential nicotinic acetylcholine receptor subunit expression in the human hippocampus.

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels composed of alpha and beta subunits with specific structural, functional and pharmacological properties. In this study the distribution of alpha3, alpha4, alpha7, beta2 and beta4 nAChR subunits in the human hippocampus was investigated using immunohistochemistry. Most pyramidal neurons, pre-alpha cells of the entorhinal cortex and dentate granule cells were immunoreactive for all subunits. Small islands of alpha7 immunoreactive cells were present in the outer presubiculum. alpha4 and beta2, and alpha3, alpha4 and beta2 immunoreactive fibre tracts were present in the stratum radiatum and subiculum, respectively, suggesting nAChRs may play a role in modulating inputs to the hippocampus via Schaffer collaterals and along the perforant pathway. Some astrocytes were immunoreactive for alpha3, alpha7 and beta4 subunits. Immunoreactivity to all subunits was noted in association with blood vessels. These results indicate the involvement of multiple nAChR subtypes in the modulation of both neuronal and non-neuronal functions in the human hippocampus.