Alzheimer's Disease Pharmacotherapy Research Articles

Discovery of a novel piperazine derivative, cmp2: a selective TRPC6 activator suitable for treatment of synaptic deficiency in Alzheimer’s disease hippocampal neurons

Alzheimer disease (AD) is characterized by progressive loss of memory. Synaptic loss is now the best correlate of cognitive dysfunction in patients with Alzheimer’s disease. Thus, restoration or limitation of synapse loss is a promising strategy for pharmacotherapy of AD. N–N substituted piperazines are widely used chemical compounds for drug interventions to treat different illnesses including CNS diseases such as drug abuse, mental and anxiety disorders. Piperazine derivatives are small molecules that are usually well tolerated and cross blood brain barrier (BBB). Thus, disubstituted piperazines are good tools for searching and developing novel disease-modifying drugs. Previously, we have determined the piperazine derivative, 51164, as an activator of TRPC6 in dendritic spines. We have demonstrated synaptoprotective properties of 51164 in AD mouse models. However, 51164 was not able to cross BBB. Within the current study, we identified a novel piperazine derivative, cmp2, that is structurally similar to 51164 but is able to cross BBB. Cmp2 binds central part of monomeric TRPC6 in similar way as hypeforin does. Cmp2 selectively activates TRPC6 but not structurally related TRPC3 and TRPC7. Novel piperazine derivative exhibits synaptoprotective properties in culture and slices and penetrates the BBB. In vivo study indicated cmp2 (10 mg/kg I.P.) reversed deficits in synaptic plasticity in the 5xFAD mice. Thus, we suggest that cmp2 is a novel lead compound for drug development. The mechanism of cmp2 action is based on selective TRPC6 stimulation and it is expected to treat synaptic deficiency in hippocampal neurons.

Regulation of mitochondrial dysfunction by estrogens and estrogen receptors in Alzheimer's disease: A focused review.

Alzheimer's disease (AD) is a neurodegenerative disorder that primarily manifests itself by progressive memory loss and cognitive decline, thus significantly affecting memory functions and quality of life. In this review, we proceed from the understanding that the canonical amyloid-β hypothesis, while significant, has faced setbacks, highlighting the need to adopt a broader perspective considering the intricate interplay of diverse pathological pathways for effective AD treatments. Sex differences in AD offer valuable insights into a better understanding of its pathophysiology. Fluctuation of the levels of ovarian sex hormones during perimenopause is associated with changes in glucose metabolism, as a possible window of opportunity to further understand the roles of sex steroid hormones and their associated receptors in the pathophysiology of AD. We review these dimensions, emphasizing the potential of estrogen receptors (ERs) to reveal mitochondrial functions in the search for further research and therapeutic strategies for AD pharmacotherapy. Understanding and addressing the intricate interactions of mitochondrial dysfunction and ERs potentially pave the way for more effective approaches to AD therapy.

Investigating the disease-modifying properties of sclerotiorin in Alzheimer's therapy using acetylcholinesterase inhibition.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused due to the damage and loss of neurons in specific brain regions. It is the most common form of dementia observed in older people. The symptoms start with memory loss and gradually cause the inability to speak and do day-to-day activities. The cost of caring for those affected individuals is huge and is probably beyond most developing countries capability. Current pharmacotherapy for AD includes compounds that aim to increase neurotransmitters at nerve endings. This can be achieved by cholinergic neurotransmission through inhibition of the cholinesterase enzyme. The current research aims to find natural substances that can be used as drugs to treat AD. The present work identifies and explains compounds with considerable Acetylcholinesterase (AChE) inhibitory activities. The pigment was extracted from the Penicillium mallochii ARA1 (MT373688.1) strain using ethyl acetate, and the active compound was identified using chromatographic techniques followed by structural confirmation with NMR. AChE inhibition experiments, enzyme kinetics, and molecular dynamics simulation studies were done to explain the pharmacological and pharmacodynamic properties. We identified that the compound sclerotiorin in the pigment has AChE inhibitory activity. The compound is stable and can bind to the enzyme non-competitively. Sclerotiorin obeys all the drug-likeliness parameters and can be developed as a promising drug in treating AD.

The protective effects of Esculentoside A through AMPK in the triple transgenic mouse model of Alzheimer's disease

BackgroundNeurofibrillary tangles comprising hyperphosphorylated tau are vital factors associated with the pathogenesis of Alzheimer's disease (AD). The elimination or reduction of hyperphosphorylated and abnormally aggregated tau is a valuable measure in AD therapy. Esculentoside A (EsA), isolated from Phytolacca esculenta, exhibits pharmacotherapeutic efficacy in mice with amyloid beta-induced AD. However, whether EsA affects tau pathology and its specific mechanism of action in AD mice remains unclear. PurposeTo investigate the roles and mechanisms of EsA in cognitive decline and tau pathology in a triple transgenic AD (3 × Tg-AD) mouse model. MethodsEsA (5 and 10 mg/kg) was administered via intraperitoneal injection to 8-month-old AD mice for eight consecutive weeks. Y-maze and novel object recognition tasks were used to evaluate the cognitive abilities of mice. Potential signaling pathways and targets in EsA-treated AD mice were assessed using quantitative proteomic analysis. The NFT levels and hippocampal synapse numbers were investigated using Gallyas-Braak silver staining and transmission electron microscopy, respectively. Western blotting and immunofluorescence assays were used to measure the expression of tau-associated proteins. ResultsEsA administration attenuated memory and recognition deficits and synaptic damage in AD mice. Isobaric tags for relative and absolute quantitation proteomic analysis of the mouse hippocampus revealed that EsA modulated the expression of some critical proteins, including brain-specific angiogenesis inhibitor 3, galectin-1, and Ras-related protein 24, whose biological roles are relevant to synaptic function and autophagy. Further research revealed that EsA upregulated AKT/GSK3β activity, in turn, inhibited tau hyperphosphorylation and promoted autophagy to clear abnormally phosphorylated tau. In hippocampus-derived primary neurons, inhibiting AMP-activated protein kinase (AMPK) activity through dorsomorphin could eliminate the effect of EsA, as revealed by increased tau hyperphosphorylation, downregulated activity AKT/GSK3β, and blocked autophagy. ConclusionsTo our knowledge, this study is the first to demonstrate that EsA attenuates cognitive decline by targeting the pathways of both tau hyperphosphorylation and autophagic clearance in an AMPK-dependent manner and it shows a high reference value in AD pharmacotherapy research.

A Review of African Medicinal Plants and Functional Foods for the Management of Alzheimer's Disease-related Phenotypes, Treatment of HSV-1 Infection and/or Improvement of Gut Microbiota.

Alzheimer's disease (AD), which is a progressive neurodegenerative disorder is the most common form of dementia globally. Several studies have suggested alteration in the gut microbiota and HSV-1 infection as contributing factors to the development of the disease. As at now, there are no AD attenuating agents and AD pharmacotherapy is focused on managing symptoms while plants used in ethnomedicine remain potential sources of drugs for the treatment of the condition. Here, we reviewed published databases for African ethnomedicinal plants and functional foods of African origin that are used in the management of AD-related phenotypes, treatment of herpes simplex virus −1 (HSV-1) and/or improvement of gut microbiota. A total of 101 unique plant species and 24 different types of traditionally prepared African functional foodstuff were identified. Of the 101 identified plant species, 50 species serve as functional foodstuffs. Twenty-three (23) of the ethnomedicinal plant families were successfully identified for the treatment and management of AD-related phenotypes and age-related dementia. Eighteen (18) African plant species from 15 families were also identified as potent remedies for HSV-1; while many African wild fruits (3 species), roots and tubers (7 species), leafy vegetables (14 species), and seaweeds (26 species) were functional foods for modifying AD-related phenotypes. It was concluded that African medicinal plants are potential sources of both AD attenuating agents and phytocompounds that may be used against HSV-1 infection and alteration of gut microbiota. Additionally, a number of African functional foods are important sources of prebiotics and probiotics.

Ameliorative Effect of Acetyl L-carnitine in Alzheimer's Disease via Downregulating of Homocysteine Levels in Hyperhomocysteinemia Induced Cognitive Deficit in Mouse Model.

The study was aimed at exploring the role of Acetyl L-Carnitine supplementation attenuating dementia and degradation of cognitive abilities in Hyperhomocysteinemia induced AD manifestations in the mouse model. Alzheimer's disease (AD) is a neurological disorder that is marked by dementia, and degradation of cognitive abilities. There is great popularity gained by natural supplements as the treatment for AD, due to the higher toxicities of synthetic drugs. Hyperhomocysteinemia causes excitotoxicity to the cortical neurons, which brought us to the point that amino acids possibly have a role in causing cholinergic deformities, which are an important etiological parameter in AD. Acetyl L-Carnitine a methyl donor with the presence of three chemically reactive methyl groups linked to a nitrogen atom was found to possess neuroprotective activity against experimental models of AD. The objective of the present investigation was to investigate and evaluate the pharmacological effect of Acetyl L-Carnitine against hyperhomocysteinemia induced Alzheimer's disease (AD) in the mouse model. The animals were divided into normal control (vehicle-treated), HHcy (dl-Homocysteine thiolactone treated) negative control, test group i.e., low dose (50mg/kg, p.o) of acetyl L-carnitine (L-ALC), high dose (100mg/kg,p.o) of acetyl L-carnitine (H-ALC), L-ALC+ SOV (Sodium orthovanadate) and H-ALC+SOV. HHcy was induced by administration of dl-Homocysteine thiolactone (dl-HCT; 1 g/kg, p.o.) on day-1 to day-15 of experimental schedule to all animals except normal control. The changes in the behaviour pattern of the animals due to neuroinflammation, and cholinergic dysfunction were examined in rotarod, novel objective recognition, passive avoidance, elevated plus maze, and morris water maze analysis. Biochemical investigation includes the estimation of total homocysteine (tHcy), Creatinine Kinase (CK), Acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and IL-6 and TNF-α. Supplementation of ALC in mouse considerably lowered the HHcy-induced AD manifestations in the experimental animals. It was found that ALC and SOV successfully diminished the behaviour abnormalities and lessened the Hcy-induced alteration in systemic Hcy levels, CK activity, and cholinergic dysfunction with improved bioenergetics in the Prefrontal cortex of the mice. ALC was found to improve the HHcy-induced cognitive disabilities which was found to be associated with the decreased systemic levels of Hcy, CK, and cholinergic abnormalities. It also combats the oxidative stress-induced neuroinflammation with diminished pro-inflammatory markers in the pre frontal cortex. The outcomes collectively indicate ALC's potential to be used as a supplementation in the pharmacotherapy of AD.

Notoginsenoside R2 reduces Aβ25-35-induced neuronal apoptosis and inflammation via miR-27a/SOX8/β-catenin axis.

Background: Alzheimer's disease (AD) has affected numerous elderly individuals worldwide. Panax notoginseng has been shown to ameliorate AD symptoms, and notoginsenoside R2 is a key saponin identified in this plant. Purpose: In the current study, we aimed to explore whether notoginsenoside R2 could improve the prognosis of AD. Methods: Herein, primary rat cortical neurons were isolated and they were treated with amyloid beta-peptide (Aβ) 25-35 oligomers. Cellular apoptosis was examined via flow cytometry and Western blotting. miR-27a and SOX8 mRNA expression levels were quantified by quantitative reverse transcription-polymerase chain reaction. Furthermore, the interaction between miR-27a and SOX8 was investigated by utilizing a dual-luciferase reporter assay. Finally, an AD mouse model was established to validate the in vitro findings. Results: Notoginsenoside R2 alleviated Aβ25-35-triggered neuronal apoptosis and inflammation. During this process, miR-27a expression was decreased by notoginsenoside R2, and miR-27a negatively modulated SOX8 expression. Furthermore, activation of SOX8 upregulated β-catenin expression, thus suppressing apoptosis and neuroinflammation. Conclusions: Our animal experiments revealed that notoginsenoside R2 enhanced the cognitive function of AD mice and inhibited neuronal apoptosis. Notoginsenoside R2 ameliorated AD symptoms by reducing neuronal apoptosis and inflammation, thus suggesting a novel direction for AD pharmacotherapy.

REPRINTED WITH PERMISSION OF IASP – PAIN 162 (2021) 999–1006: Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease

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Ang(1-7) exerts Nrf2-mediated neuroprotection against amyloid beta-induced cognitive deficits in rodents.

Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive deficits in an individual. Ang(1-7) exhibits neuroprotection against amyloid beta (Aβ)-induced mitochondrial dysfunction and neurotoxicity in experimental conditions. Further, Ang(1-7) also exhibits nrf2-mediated antioxidant activity in experimental conditions. However, its therapeutic role on nrf2-mediated mitochondrial function is yet to be established in the Aβ-induced neurotoxicity. The experimental dementia was induced in the male rats by intracerebroventricular administration of Aβ(1-42) on day-1 (D-1) of the experimental schedule of 14days. Ang(1-7) was administered once daily from D-1 toD-14 to the Aβ-challenged rodents. Ang(1-7) attenuated Aβ-induced increase in escape latency and decrease in the time spent in the target quadrant during Morris water maze and percentage of spontaneous alteration behavior during Y-maze tests in the rats. Further, Ang(1-7) attenuated Aβ-induced cholinergic dysfunction in terms of decrease in the level of acetylcholine and activity of choline acetyltransferase, and increase in the activity of acetylcholinesterase, and increase in the level of Aβ in rat hippocampus, pre-frontal cortex and amygdala. Furthermore, Ang(1-7) reversed Aβ-induced decrease in the mitochondrial function, integrity and bioenergetics in all brain regions. Additionally, Ang(1-7) attenuated Aβ-induced increase in the extent of apoptosis and decrease in the level of heme oxygenase-1 in all selected brain regions. Trigonelline significantly abolished the therapeutic effectiveness of Ang(1-7) on Aβ-induced alterations in the behavioral, neurochemicals and molecular observations in the animals. Ang(1-7) may exhibit nrf2-mediated neuroprotection in these rodents. Hence, Ang(1-7) could be a potential therapeutic option in the pharmacotherapy of AD.

Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease.

Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease.

Donepezil and Rivastigmine: Pharmacokinetic Profile and Brain-targeting After Intramuscular Administration in Rats.

Current palliative pharmacotherapy of Alzheimer’s disease based on the cholinergic hypothesis led to the development of four cholinesterase inhibitors. These compounds can bring prolongation of the symptom-free period in some patients. This is the first report directly comparing donepezil and rivastigmine plasma and brain levels in in-vivo study. Donepezil and rivastigmine were applied i.m. to rats; the dose was calculated from clinical recommendations. The samples were analysed on an Agilent 1260 Series LC with UV/VIS detector. An analytical column (Waters Spherisorb S5 W (250 mm × 4.6 i.d.; 5 μm particle size)) with guard column (Waters Spherisorb S5 W (30 mm × 4.6 mm i.d.)) was used. The mobile phase contained acetonitrile and 50 mM sodium dihydrogen phosphate (17:83; v/v); pH 3.1. The LLOQ in rat plasma was 0.5 ng/mL for donepezil and 0.8 ng/mL for rivastigmine, and the LLOQ in rat brain was 1.0 ng/mL for donepezil and 1.1 ng/mL for rivastigmine. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. Maximum brain concentration after i.m. administration was reached in the 36 (8.34 ± 0.34 ng/mL) and 17 minute (6.18 ± 0.40 ng/mL), respectively for donepezil and rivastigmine. The differences in brain profile can be most easily expressed by plasma/brain AUCtotal ratios: donepezil ratio in the brain was nine-times higher than in plasma and rivastigmine ratio was less than two-times higher than in plasma.

In silico and in vitro studies of two non-imidazole multiple targeting agents at histamine H3 receptors and cholinesterase enzymes.

Recently, multi-target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H3 receptors (H3 Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual-acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H3 R antagonistic activity combined with anticholinesterase properties of two previously computationally identified lead compounds, that is, compound 3 (6-chloro-N-methyl-N-[3-(4-methylpiperazin-1-yl)propyl]-1H-indole-2-carboxamide) and compound 4 (7-chloro-N-[(1-methylpiperidin-3-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide), was tested. Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (compound 3: H3 R EC50 =0.73nM; compound 4: H3 R EC50 =31nM) and micromolar values (compound 3: AChE IC50 =9.09µM, BuChE IC50 =21.10µM; compound 4: AChE IC50 =8.40µM, BuChE IC50 =4.93µM) for H3 R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H3 R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy.

Exendin-4 attenuates brain mitochondrial toxicity through PI3K/Akt-dependent pathway in amyloid beta (1–42)-induced cognitive deficit rats

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, disorientation and gradual deterioration of intellectual ability. In the pharmacotherapy of AD, the mitochondrial protective activity of Exendin-4 in experimental studies is yet to be established though its effectiveness is demonstrated in these patients. Therefore, the mitochondria protective activity of Exendin-4 (5 μg/kg, i.p.) was investigated in hippocampus and pre-frontal cortex (PFC) of AD-like animals. The amyloid beta (Aβ) was injected through bilateral intracerebroventricular route into lateral ventricles to induce AD-like manifestations in the male rats. Exendin-4 significantly attenuated Aβ-induced memory-deficits in the Morris water maze and Y-maze test protocols. Exendin-4 significantly decreased Aβ-induced increase in the level of Aβ in both brain regions. Exendin-4 significantly increased Aβ-induced decrease in acetylcholine level and activity of cholineacetyl transferase in all brain regions. Moreover, Exendin-4 significantly decreased Aβ-induced increase in the activity of acetylcholinestrase in both the brain regions. E4 significantly increased Aβ-induced decrease in mitochondrial function, integrity, respiratory control rate and ADP/O in all brain regions. Further, Exendin-4 significantly decreased Aβ-induced increase in the mitochondrial complex enzyme-I, IV and V activities in all brain regions. Furthermore, Exendin-4 significantly increased Aβ-induced decrease in the level of phosphorylated Akt and the ratio of phosphorylated Akt to Akt in both brain regions. However, LY294002 diminished the therapeutic effects of Exendin-4 on behavioral, biochemical and molecular observations in AD-like animals. Pearson's analysis showed that the attributes of mitochondrial dysfunction (MMP and RCR) exhibited significant correlation to the loss in memory formation, level of Aβ and cholinergic dysfunction in these animals. Thus, it can be speculated that Exendin-4 may mitigate AD-like manifestations including mitochondrial toxicity perhaps through PI3K/Akt-mediated pathway in the experimental animals. Hence, Exendin-4 could be a potential therapeutic alternative candidate in the management of AD.

Current and Future Treatments in Alzheimer's Disease.

The foundation of current Alzheimer's disease (AD) treatment involves pharmacological and nonpharmacological management and care planning predicated on patient-centered psychoeducation, shared goal-setting, and decision-making forged by a strong triadic relationship between clinician and the patient-caregiver dyad. Food and Drug Administration (FDA) approved AD medications, cholinesterase-inhibitors (ChEIs), and the N-methyl-d-aspartate (NMDA) antagonist memantine, when utilized as part of a comprehensive care plan, while generally considered symptomatic medications, can provide modest "disease course-modifying" effects by enhancing cognition, and reducing loss of independence. When combined, pharmacologic and nonpharmacologic treatments can meaningfully mitigate symptoms and reduce clinical progression and care burden. AD pharmacotherapy first involves identification and elimination of potentially harmful medications and supplements. First line treatment for neuropsychiatric symptoms and problem behaviors is nonpharmacological and involves psychoeducation, trigger identification, and implementation, iterative evaluation, and adjustment of behavioral and environmental interventions. Intensive research efforts are underway to develop more accurate and practical AD diagnostic biomarkers and clinical tools and better therapeutics. Ongoing research studies for primary and secondary prevention of AD and clinical trials evaluating symptomatic and disease-modifying treatments in symptomatic AD are directed at diverse therapeutic targets including neurochemicals, amyloid and tau pathological processes, mitochondria, inflammatory pathways, neuroglia, and multimodal lifestyle interventions.

Farmakoterapie Alzheimerovy demence a přidružených neuropsychiatrických symptomů - 1. část

Alzheimerova choroba je nejcastějsi přicinou demence. Pro ucelnou lecbu je třeba vcasna a přesna diagnostika. K symptomaticke terapii jsou využivany inhibitory acetylcholinesterazy, v pozdějsich fazich take memantin. Soucasti demence bývaji neuropsychiatricke symptomy, jsou castou přicinou institucionalizace a stresu pacienta i pecovatelů. Snažime se zjistit a odstranit jejich přicinu, v lecbě preferujeme nefarmakologický přistup. Při neucinnosti režimových opatřeni lze volit vybrana antidepresiva, antipsychotika, anxiolytika, připadně dalsi latky. Nasledujici přehled pojednava o rozdilech v ucinnosti a bezpecnosti mezi jednotlivými latkami a upozorňuje na možna rizika, ktera jsou s terapii spojena.

Pharmacist’s Role in Pharmacotherapeutic Management of Alzheimer’s Disease

Alzheimer Disease (AD) characterized by the progressive cognitive and functional impairment, is the most common form of dementia affecting people worldwide. In this study, we aimed to investigate the profile of patients with AD, the perception of caregivers about the disease and the role of pharmacist in the pharmacotherapy of AD by implementing a questionnaire for the caregivers of 44 patients with AD. 70% of the evaluated patients with AD is female gender and in 52% of the cases, hypertension co-exists with AD. The combination of memantine/donepezil (34%) was found the most commonly used pharmacological treatment in the patients which was associated with various adverse effects such as headache, insomnia, fatigue, and hallucinations. An average of 70% of the caregivers benefit from the pharmacists in regard to the use of drugs (94%), information about disease and side effects (48%) and drug-drug interactions (42%). Additionally, the 77% of caregivers who benefit from pharmacists were well satisfied with this support. In conclusion, patients with AD and their caregivers need a professional assistance regarding the use of drugs and modalities how to fight with the disease. Pharmacists play a significant role in both following the pharmacotherapy of AD patients and the education of caregivers. Thus, pharmacist’s role in the management of rational pharmacotherapy should be strengthened by providing a continued educational support.

Knowledge and pharmacological management of Alzheimer's disease by managing community pharmacists: a nationwide study.

Background Managing community pharmacists can play a leading role in supporting community dwelling individuals with Alzheimer's disease and their caregivers. Objective The main purpose of this study was to assess knowledge of managing community pharmacists towards Alzheimer's disease and its pharmacological management. Setting Community pharmacies in the Maltese islands. Method A nationwide survey was conducted with full-time managing community pharmacists in possession of a tertiary education degree in pharmacy studies. The level of knowledge was investigated using the Alzheimer's Disease Knowledge Scale and the Alzheimer's Disease Pharmacotherapy Measure. Participants were also asked to rate a number of statements related to disease management. Results Maltese managing community pharmacists (57% response rate) had inadequate knowledge on risk factors, caregiving issues and pharmacological management of Alzheimer's disease. Age and number of years working in a community pharmacy setting were found to be negatively correlated with increased knowledge. Conclusion The findings highlight the need of providing training and continued educational support to managing community pharmacists in order to provide quality advice to individuals with dementia and their caregivers in the community.

Current pharmacotherapy and putative disease-modifying therapy for Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease of the central nervous system correlated with the progressive loss of cognition and memory. β-Amyloid plaques, neurofibrillary tangles and the deficiency in cholinergic neurotransmission constitute the major hallmarks of the AD. Two major hypotheses have been implicated in the pathogenesis of AD namely the cholinergic hypothesis which ascribed the clinical features of dementia to the deficit cholinergic neurotransmission and the amyloid cascade hypothesis which emphasized on the deposition of insoluble peptides formed due to the faulty cleavage of the amyloid precursor protein. Current pharmacotherapy includes mainly the acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor agonist which offer symptomatic therapy and does not address the underlying cause of the disease. The disease-modifying therapy has garnered a lot of research interest for the development of effective pharmacotherapy for AD. β and γ-Secretase constitute attractive targets that are focussed in the disease-modifying approach. Potentiation of α-secretase also seems to be a promising approach towards the development of an effective anti-Alzheimer therapy. Additionally, the ameliorative agents that prevent aggregation of amyloid peptide and also the ones that modulate inflammation and oxidative damage associated with the disease are focussed upon. Development in the area of the vaccines is in progress to combat the characteristic hallmarks of the disease. Use of cholesterol-lowering agents also is a fruitful strategy for the alleviation of the disease as a close association between the cholesterol and AD has been cited. The present review underlines the major therapeutic strategies for AD with focus on the new developments that are on their way to amend the current therapeutic scenario of the disease.

Current and novel therapeutic molecules and targets in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder in which the death of brain cells causes memory loss and cognitive decline, i.e., dementia. The disease starts with mild symptoms and gradually becomes severe. AD is one of the leading causes of mortality worldwide. Several different hallmarks of the disease have been reported such as deposits of β-amyloid around neurons, hyperphosphorylated tau protein, oxidative stress, dyshomeostasis of bio-metals, low levels of acetylcholine, etc. AD is not simple to diagnose since there is no single diagnostic test for it. Pharmacotherapy for AD currently provides only symptomatic relief and mostly targets cognitive revival. Computational biology approaches have proved to be reliable tools for the selection of novel targets and therapeutic ligands. Molecular docking is a key tool in computer-assisted drug design and development. Docking has been utilized to perform virtual screening on large libraries of compounds, and propose structural hypotheses of how the ligands bind with the target with lead optimization. Another potential application of docking is optimization stages of the drug-discovery cycle. This review summarizes the known drug targets of AD, invivo active agents against AD, state-of-the-art docking studies done in AD, and future prospects of the docking with particular emphasis on AD.

Detection of acetylcholinesterase-inhibiting natural products from Illicium angustisepalum by bioautographic screening

Alzheimer's disease (AD) is the most common type of dementia and a leading neurodegenerative disorder. According to the cholinergic hypothesis, memory impairment in AD patients results from the dysfunctions in the central neurotransmission of acetylcholine. Inhibitors of acetylcholinesterase (AChE) currently form the basis of pharmacotherapy of AD. In the course of a search for natural AChE inhibitors, Illicium angustisepalum A.C. Smith (Schisandraceae) was found to be active by using a bioautographic assay. Since former studies have identified the Illicium genus to be a potential source of AChE inhibitors, this under-studied member of Illicium was further investigated. In the present study, an essential oil and four extracts (i.e., ethyl acetate, butanol, petroleum ether and water extracts) of I. angustisepalum were tested for AchE-inhibiting activity, and positive results were observed in the essential oil and the ethyl acetate fraction. Isolation work is underway and this poster will report the most recent findings in the attempt to identify active principles based on bioautographic detection.