Role of nicergoline in corneal wound healing in diabetic rats.

BACKGROUND: To investigate the effect of nicergoline on the rate of complete corneal ulcer reepithelialization (CCUR) in diabetic rats with diabetic keratopathy. METHODS: Forty-eight streptozotocin-induced diabetic rats were randomly divided into two groups. The experimental group (n = 24) received nicergoline (10 mg.kg- 1.day- 1), while the control group (n = 24) received a placebo. A corneal epithelial defect was induced using a corneal diamond burr, and defect area was compared at time points of 0, 12, 24, 48 and 72 h after the injury using image analysis software. The probability of CCUR within 72 h was assessed using the Kaplan-Meier survival analysis log-rank test. RESULTS: When compared, 4 of the 24 rats (17%) in the placebo group and 12 of the 24 rats (50%) in the nicergoline group were found to have CCUR within 72 h (log-rank = 0.027). Cox regression analysis found no effect of the covariates blood glucose (P = 0.601) or weight (P = 0.322) on the corneal reepithelialization (survival) curve. CONCLUSIONS: Nicergoline increased wound healing rates relative to placebo and may therefore be investigated as a treatment option in diabetic keratopathy.

Nerve growth factor in dogs: Assessment of two immunoassays and selected ocular parameters following a nicergoline challenge per os.

Impairment of corneal nerves can result in the development of ocular surface diseases such as aqueous tear deficiency and neurotrophic keratopathy. This study investigates oral nicergoline, an α-adrenoceptor antagonist shown to enhance endogenous secretion of nerve growth factor (NGF) by the lacrimal gland, as a potential therapy for these conditions. Five female spayed Beagle dogs received a 2-week course of oral nicergoline (10 mg twice daily). Drug safety was evaluated with ophthalmic and physical examinations, blood pressure monitoring, bloodwork, and urinalysis. The effect of nicergoline on the ocular surface was assessed with corneal esthesiometry, Schirmer tear test-1, and tear film breakup time. Drug effect on NGF levels was assessed by collecting tears and blood at baseline and completion of therapy using a bead-based immunoassay and an enzyme-linked immunosorbent assay. Although nicergoline was well tolerated in all dogs, it did not have a significant impact on corneal sensitivity, tear production, or tear stability. Of note, NGF was below the limit of quantification in all tear samples and was only detected in 8/20 serum samples with no significant difference between levels at baseline (189.4 ± 145.1 pg/mL) and completion of therapy (149.4 ± 79.4 pg/mL). Further validation of NGF analytical assays is warranted before nicergoline is investigated in clinical patients.

Dihydrogen Bond in the Aminoborane Complex of a Nicergoline Intermediate.

An aminoborane side product from the nicergoline manufacture process was identified by single-crystal X-ray diffraction. As boranes of pharmaceutical molecules are quite rare, the binding potential of the BH3 group was investigated and compared with similar compounds using Cambridge Structural Database (CSD). Surprisingly, the packing was stabilized by a dihydrogen bond, which triggered a false alert for too-short contact of hydrogen atoms in IUCR checkCIF. As the dihydrogen bond concept is not widely known, such an alert might mislead crystallographers to force -CH3 optimal geometry to -BH3 groups. The B-H distances equal to or less than 1.0 Å (17% of the CSD structures) are substantially biased when analyzing the structures of aminoborane complexes in CSD. To conduct proper searching, B-H bond length normalization should be applied in the CSD search.

Neurotransmitter signaling pathways required for normal development in Xenopus laevis embryos: a pharmacological survey screen.

Neurotransmitters are not only involved in brain function but are also important signaling molecules for many diverse cell types. Neurotransmitters are widely conserved, from evolutionarily ancient organisms lacking nervous systems through man. Here, results are reported from a loss- and gain-of-function survey, using pharmacological modulators of several neurotransmitter pathways to examine possible roles for these pathways in normal embryogenesis. Applying reagents targeting the glutamatergic, adrenergic and dopaminergic pathways to embryos of Xenopus laevis from gastrulation to organogenesis stages, we observed and quantified numerous malformations, including craniofacial defects, hyperpigmentation, muscle mispatterning and miscoiling of the gut. These data implicate several key neurotransmitters in new embryonic patterning roles, reveal novel earlier stages for processes involved in eye development, suggest new targets for subsequent molecular-genetic investigation, and highlight the necessity for in-depth toxicology studies of psychoactive compounds to which human embryos might be exposed during pregnancy.

Effect of four different size reduction methods on the particle size, solubility enhancement and physical stability of nicergoline nanocrystals.

Nicergoline, a poorly soluble active pharmaceutical ingredient, possesses vaso-active properties which causes peripheral and central vasodilatation. In this study, nanocrystals of nicergoline were prepared in an aqueous solution of polysorbate 80 (nanosuspension) by using four different laboratory scale size reduction techniques: high pressure homogenization (HPH), bead milling (BM) and combination techniques (high pressure homogenization followed by bead milling HPH + BM, and bead milling followed by high pressure homogenization BM + HPH). Nanocrystals were investigated regarding to their mean particles size, zeta potential and particle dissolution. A short term physical stability study on nanocrystals stored at three different temperatures (4, 20 and 40 °C) was performed to evaluate the tendency to change in particle size, aggregation and zeta potential. The size reduction technique and the process parameters like milling time, number of homogenization cycles and pressure greatly affected the size of nanocrystals. Among the techniques used, the combination techniques showed superior and consistent particle size reduction compared to the other two methods, HPH + BM and BM + HPH giving nanocrystals of a mean particle size of 260 and 353 nm, respectively. The particle dissolution was increased for any nanocrystals samples, but it was particularly increased by HPH and combination techniques. Independently to the production method, nicergoline nanocrystals showed slight increase in particle size over the time, but remained below 500 nm at 20 °C and refrigeration conditions.

Blocking α1 Adrenergic Receptor as a Novel Target for Treating Alzheimer's Disease.

While amyloidopathy and tauopathy have been recognized as hallmarks in Alzheimer's disease (AD) brain, recently, increasing lines of evidence have supported the pathological roles of cerebrovascular changes in the pathogenesis and progression of AD. Restoring or ameliorating the impaired cerebrovascular function during the early phase of the disease may yield benefits against the cognitive decline in AD. In the present study, we evaluated the potential therapeutic effects of nicergoline [NG, a well-known α1 adrenergic receptor (ADR) blocker and vasodilator] against AD through ameliorating vascular abnormalities. Our in vitro data revealed that NG could reverse ß-amyloid1-42 (Aß1-42)-induced PKC/ERK1/2 activation, the downstream pathway of α1-ADR activation, in α1-ADR-overexpressed N2a cells. NG also blocked Aß1-42- or phenylephrine-induced constrictions in isolated rat arteries. All these in vitro data may suggest ADR-dependent impacts of Aß on vascular function and the reversal effect of NG. In addition, the ameliorating impacts of NG treatment on cerebral vasoconstriction, vasoremodeling, and cognitive decline were investigated in vivo in a PSAPP transgenic AD mouse model. Consistent with in vitro findings, the chronic treatment of NG significantly ameliorated the cerebrovascular dysfunctions and Aß plaque depositions in the brain. Moreover, an improved cognitive performance was also observed. Taken together, our findings supported the beneficial effects of NG on AD through adrenergic-related mechanisms and highlighted the therapeutic potential of α1-adrenergic vasomodulators against AD pathologies.

[Study of the effect of Unifuzol on cognitive impairment and damage to the hippocampus and cerebral cortex during course administration to rats with bilateral stenosis of the common carotid arteries, causing chronic circulatory failure]. / Vliyanie preparata Unifuzol na sostoyanie kognitivnykh funktsii v usloviyakh eksperimental'nogo khronicheskogo narusheniya mozgovogo krovoobrashcheniya.

OBJECTIVE: To study the effect of Unifuzol (L-arginine sodium succinate) on cognitive impairment, cerebral blood flow, and damage to the tissues of the hippocampus and cerebral cortex during a 10-day course of administration to rats with chronic cerebral ischemia (CCI) caused by bilateral stenosis of the common carotid arteries (CCA). MATERIAL AND METHODS: The study was conducted on male rats with CCI caused by bilateral stenosis of the CCA by 60%. 40 days after surgery, rats received Unifusol (21, 42 and 84 ml/kg), nicergoline (10 mg/kg), citicoline (500 mg/kg) or placebo (0.9% NaCl) for 10 days. Next, cognitive impairments were assessed in the Morris Water Maze and the New Object Recognition (NOR) test, as well as the level of motor and exploratory activity in the Open Field test. The level of cerebral blood flow was determined immediately after the CCA stenosis and at the end of the experiment. Animals were euthanized in a CO2 incubator, after which the brain was removed and subjected to morphometric analysis. RESULTS: In animals that were modeled with CCA stenosis, pronounced behavioral and cognitive impairments occurred as a result of a decrease in blood flow in the vessels of the brain and subsequent changes in the tissues of the hippocampus and the cerebral cortex. Intravenous course administration of Unifuzol at doses of 42 and 84 ml/kg to animals with CCI was comparable in efficiency to nicergoline and citicoline, which was expressed in greater preservation of the cognitive abilities of animals in the Morris Water Maze and NOR tests. In the Open Field test, animals injected with Unifusol at doses of 42 and 84 ml/kg performed more acts of motor and exploratory activity than animals from the placebo group, and had a higher level of cerebral blood flow (compared to animals that were injected with citicoline). Based on the results of a morphological study, it was found that the most significant neuroprotective effect was provided by nicergoline and Unifuzol (at doses of 42 and 84 ml/kg). CONCLUSION: Unifuzol at a course of administration at doses of 42 and 84 ml/kg, comparable to the reference drugs nicergoline and citicoline, reduces the severity of psychoneurological deficit in animals with CCI, comparable to them improves the microcirculation of brain tissues, preventing damage to brain tissues.

A clinical trial of nicergoline to prevent temporary threshold shift.

Objective: To evaluate the effectiveness of nicergoline to prevent temporary threshold shift (TTS) in military personnel. Study Design: A randomized control trial. Methods: Two hundred and twenty-four participants were enrolled. Nicergoline 30 mg twice daily intake was prescribed to the study group (n = 119) for 3 weeks. The placebo was prescribed to the control group (n = 105) for 3 weeks, as well. Audiometric thresholds were measured at baseline and within 24 h after the participants attended a 1-day weapons firing practice. During the firing practice, all participants had to wear foam earplugs. The TTS was assessed by using a variety of published significant threshold shift (STS) definitions. Additionally, the effects of the treatment group on the magnitude of pre- to postexposure threshold shifts were estimated. Tinnitus and other adverse effects of the medication were recorded. Results: The incidence of STS was 65.4% from the study group and 75% from the control group. The negative STS (thresholds improved) was 68.6% from the study group and 44.7% from the control group. The positive STS (thresholds worsened) from the study group and the control group was 31.4% and 55.3%, respectively. The effect of treatment in participants receiving nicergoline demonstrated significant coefficients (change in dB) in both ears (p = .001). The mean different threshold of participants receiving nicergoline showed negative STS in all tested frequencies without statistical significance. However, the mean different threshold of participants receiving a placebo showed positive STS with statistical significance. Additionally, there were 16 ears detecting a warning sign of permanent hearing loss. These participants from the control group presented a longer duration of tinnitus (p = .042). Moreover, the serious adverse effects of nicergoline were considerably low. Conclusion: The study results suggest that nicergoline may attenuate noise-related TTS and tinnitus, and justify further investigation on the effectiveness of this drug as an otoprotectant. Level of Evidence: 2.

[Vascular cognitive impairment]. / Sosudistye kognitivnye narusheniya.

Vascular cognitive impairment is considered the second most common cause of dementia after Alzheimer's disease. One of the most significant factors leading to vascular dementia is stroke, which increases the risk of developing dementia by about 2 times. Delayed-onset post-stroke dementia is mainly due to severe small vessel disease, recurrent stroke, or concomitant Alzheimer's disease. Among the many mechanisms involved in the development of vascular cognitive impairment, cerebral small vessel disease is perhaps the most common, contributing to cognitive impairment independent of stroke. An important feature of small vessel disease is its steady progression. The cognitive decline in cerebrovascular disease, including small vessel disease, is also usually gradual and gradual, progresses slowly, and the underlying defect extends to processing speed, complex attention, and fronto-executive functions. Vascular cognitive impairments are quite heterogeneous in nature, while having a negative impact on all major cognitive domains. Patient management should include the earliest possible diagnosis of cognitive impairment and the appointment of timely therapy. One of the drugs that has been successfully used to treat vascular cognitive impairment is nicergoline (Sermion). The clinical efficacy of the drug is achieved due to the improvement of cerebral blood flow, a positive effect on cholinergic neurotransmission and neuroprotective action.

Use of Nicergoline as Adjunctive Treatment of Neurotrophic Keratitis in Routine Clinical Practice: A Case Series.

PURPOSE: To describe the effectiveness and safety of nicergoline in patients with epithelial corneal defect or corneal ulcer due to neurotrophic keratitis (NK). METHODS: A prospective case series review was performed in 14 patients with NK who started treatment with nicergoline as an off-label prescription from January to November 2020. Patients with a epithelial defect or corneal ulcer due to NK were treated with oral nicergoline. RESULTS/SERIAL CASES: Complete corneal healing was observed in 10 (71.4%) of the 14 patients after 25.6 ± 26.60 days (range 7-90) with nicergoline. In three (21.5%) patients wound healing was not achieved, and one patient (7.1%) was lost to follow-up. The mean time between diagnosis and the starting of nicergoline was 10.92 ± 8.85 days (0-28). No adverse effects of nicergoline were observed. CONCLUSION: Nicergoline as an adjunctive treatment for NK showed a potential use in the healing of epithelial defect in real-life clinical practice.

[Efficacy of Sermion in the treatment of tinnitus noise in patients with chronic cerebrovascular pathology]. / Effektivnost' Sermiona v lechenii shuma v ushakh u patsientov s khronicheskoi tserebrovaskulyarnoi patologiei.

Noise in the ears or tinnitus is one of the earliest and most frequent non-cognitive manifestations of chronic cerebral ischemia (CCI) and is the most difficult clinical phenomenon for therapeutic intervention. OBJECTIVE: Of an open observational noncomparative clinical study was to study in patients with CCI and tinnitus and/or head the efficacy and tolerability of Sermion in a daily dose of 30 mg for 6 months. MATERIAL AND METHODS: 56 patients (51.1±8.7 years) were clinically and neurologically examined using standard questionnaires to analyze the severity of tinnitus and its impact on daily life and the level of patient distress associated with noise, and to study the quality of life using the SF-36 questionnaire. All patients independently assessed the therapy satisfaction index. RESULTS AND CONCLUSION: The safety, good tolerance and obvious clinical effect were shown when using the drug Sermion. The best results were obtained with the use of Sermion for 6 months in relation to the severity of tinnitus, the degree of its influence on daily activity, the level of distress and an increase in the quality of life of patients, as well as a significant improvement in well-being and cognitive functions in almost all subjects. It has been shown that after an adequate course of therapy and after 3 months, the therapeutic efficacy of Sermion is preserved, and the patients themselves were more satisfied with this remedy after 6 months of treatment. The data obtained suggest a wider use of Sermion in patients with cerebrovascular diseases and tinnitus and/or head, the use of which allows a safe, effective and pathogenetically reasonable effect on the existing disorders in these patients.

Sesame Oil-Based Nanostructured Lipid Carriers of Nicergoline, Intranasal Delivery System for Brain Targeting of Synergistic Cerebrovascular Protection.

Nicergoline (NIC) is a semisynthetic ergot alkaloid derivative applied for treatment of dementia and other cerebrovascular disorders. The efficacy of sesame oil to slow and reverse the symptoms of neurodegenerative cognitive disorders has been proven. This work aimed to formulate and optimize sesame oil-based NIC-nanostructured lipid carriers (NIC-NLCs) for intranasal (IN) delivery with expected synergistic and augmented neuroprotective properties. The NIC-NLC were prepared using sesame oil as a liquid lipid. A three-level, three-factor Box-Behnken design was applied to statistically optimize the effect of sesame oil (%) of the total lipid, surfactant concentration, and sonication time on particle size, zeta potential, and entrapment efficacy as responses. Solid-state characterization, release profile, and ex vivo nasal permeation in comparison to NIC solution (NIC-SOL) was studied. In vivo bioavailability from optimized NIC-NLC and NIC-SOL following IN and IV administration was evaluated and compared. The optimized NIC-NLC formula showed an average particle size of 111.18 nm, zeta potential of -15.4 mV, 95.11% entrapment efficacy (%), and 4.6% loading capacity. The NIC-NLC formula showed a biphasic, extended-release profile (72% after 48 h). Permeation of the NIC-NLC formula showed a 2.3 enhancement ratio. Bioavailability studies showed a 1.67 and 4.57 fold increase in plasma and brain following IN administration. The results also indicated efficient direct nose-to-brain targeting properties with the brain-targeting efficiency (BTE%) and direct transport percentage (DTP%) of 187.3% and 56.6%, respectively, after IN administration. Thus, sesame oil-based NIC-NLC can be considered as a promising IN delivery system for direct and efficient brain targeting with improved bioavailability and expected augmented neuroprotective action for the treatment of dementia.

The Efficacy of Sertraline, Escitalopram, and Nicergoline in the Treatment of Depression and Apathy in Alzheimer's Disease: The Okayama Depression and Apathy Project (ODAP).

BACKGROUND: Neuropsychiatric symptoms of dementia such as depression and apathy in patients with Alzheimer's disease (AD) are associated with a lower quality of life. OBJECTIVE: We aimed to determine the efficacy of two antidepressants and one antipathy drug in the treatment of depression and apathy in AD patients. METHODS: In the present study, we evaluated the efficacy of sertraline (n = 11; average dose = 31.8 mg), escitalopram (n = 13; average dose = 7.3 mg), and nicergoline (n = 9; average dose = 14.5 mg) in treating depression and apathy over a period of 3 months (M).The 33 patients with AD demonstrated high Geriatric Depression Scale (GDS) (>5) or a high Apathy Scale (AS) (>16) scores. RESULTS: The patients receiving escitalopram treatment showed a significant improvement in GDS score from baseline (8.2±3.5) to 3 M (5.7±2.6, p = 0.04), and the patients receiving sertraline treatment showed a significant improvement in AS score from baseline (20.8±5.2) to 3 M (16.8±6.1, p = 0.05); however, no significant changes were noted in patients receiving nicergoline. CONCLUSION: These results provide novel information on the efficacy of sertraline and escitalopram in the treatment of apathy and depression, respectively, in patients with AD.

Efficacy of nicergoline treatment in Parkinson's disease associated with dementia.

Parkinson's disease (PD) has a variable spectrum of cognitive impairment. However, there are no clear evident-based management guidelines for PD with dementia (PDD). Alternative treatments for PDD are therefore required. We conducted this longitudinal study to evaluate the efficacy of nicergoline in treating PDD by analyzing changes in regional cerebral blood flow (rCBF) and neuropsychological tests before and after nicergoline administration. A total of nine PDD patients who received nicergoline therapy (PDD + N) and 14 PD patients who did not receive nicergoline therapy (PDD - N) underwent single photon emission computed tomography (SPECT) and clinical assessments at baseline and 12-month follow-up visits. The PDD + N received nicergoline at 30 mg twice per day. Changes in rCBF were compared between the groups, and correlation analysis was performed to determine possible relationship between rCBF and clinical characteristics. There were no significant differences in rCBF between the two groups at baseline. Although changes in cognitive test scores and the motor severity scale were not significantly different between baseline and the 12-month follow-up within groups, rCBF was lower in both the temporal and inferior frontal restricted areas in the PDD - N group than the PDD + N at the 12-month follow-up visit. In conclusions, nicergoline appears to delay the speed of deterioration of cognitive function in patients with PDD based on our observation of decreased rCBF in the temporal regions and inferior frontal regions of PDD - N patients compared to PDD + N patients after 12-month of nicergoline therapy. Therefore, we cautiously suggest that nicergoline administration in PDD patients may slow progression of cognitive impairment in affected brain regions.

Changes in the Solid State of Nicergoline, a Poorly Soluble Drug, Under Different Grinding and Environmental Conditions: Effect on Polymorphism and Dissolution.

Nicergoline native crystals (Form I) were subjected to different grinding methods for 15, 30, 45, and 60 min: Method A, grinding at 20°C under air atmosphere; Method B, grinding in presence of liquid nitrogen under air atmosphere; Method C, grinding at 20°C under nitrogen atmosphere; and Method D, grinding in presence of liquid nitrogen under nitrogen atmosphere. Scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry, thermogravimetry, and infrared spectroscopy were used to follow changes in the particle size and in crystalline structures. Batches from Methods A and C underwent partial amorphization immediately after grinding; Form II was obtained by heating these partially amorphous forms or after spontaneous crystallization after 1 and 5 months storage. Method B promoted the hydration of nicergoline to a monohydrate form. Batch D was stable under grinding and neither amorphization nor hydration were observed. The best intrinsic dissolution rate was that of metastable Form II, followed by Form I, while the worst was that of the Method B monohydrate form. The slowest particle dissolution was observed for hydrated particles, because of the lowest IDR, while the most rapid was exhibited by batch D, because of the very small particle size.

Ameliorative effect of nicergoline on cognitive function through the PI3K/AKT signaling pathway in mouse models of Alzheimer's disease.

Alzheimer's disease is one of the most common age­associated diseases that frequently leads to memory disorders, cognitive decline and dementia. Evidence suggests that nicergoline serves an important role in the apoptosis of hippocampal cells, memory recovery, cognitive function and neuronal survival. However, the signaling pathway affected by nicergoline treatment remains to be elucidated. The purpose of the present study was to investigate the role of nicergoline in the cognitive competence of a mouse model of Alzheimer's disease. The apoptosis rates of hippocampal cells were studied in mice with Alzheimer's disease treated with nicergoline compared with the negative control. Apoptosis­associated gene expression levels in hippocampal cells, and hippocampus area, were analyzed in the experimental mice. Visual attention and inhibitory control were assessed and neural counting was performed in brain regions of interest. The phosphatidylinositol 3­kinase (PI3K)/RAC­α serine/threonine­protein kinase (AKT) signaling pathway was additionally analyzed in hippocampal cells following treatment with nicergoline. The results of the present study demonstrated that nicergoline ameliorated apoptosis in hippocampal cells and hippocampus tissue in 3xTg­AD mice with Alzheimer's disease. The data indicated that apoptosis­associated genes, including caspase­3, BCL2 associated X, BH3 interacting domain death agonist and caspase­9, were downregulated in hippocampal cells isolated from nicergoline-treated experimental mice. In addition, the expression levels of inflammatory factors, in addition to oxidative stress, were decreased in hippocampal cells treated with nicergoline. Additionally, amyloid precursor protein accumulation was cleared in the hippocampal area in nicergoline­treated mice. Nicergoline inhibited neuronal loss and prevented cognitive impairment through the restoration of learning/memory ability. It was additionally demonstrated in the present study that nicergoline improved motor attention impairment and cognitive competence in hippocampal cells by acting on the PI3K/AKT signaling pathway. Therefore, memory recovery, cognitive function and neuronal survival were repaired by nicergoline via inhibition of the PI3K/AKT signaling pathway, suggesting that nicergoline may be an efficient drug for the clinical treatment of patients with Alzheimer's disease.

Features and outcomes of drugs for combination therapy as multi-targets strategy to combat Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD), a deleterious neurodegenerative disorder that impairs memory, cognitive functions and may lead to dementia in late stage of life. The pathogenic cause of AD remains incompletely understood and FDA approved drugs are partial inhibitors rather than curative. Most of drugs are synthetic or natural products as galanthamine is an alkaloid obtained from Galanthus spp. Huperzine A, an alkaloid found in Huperzia spp., gingkolides a diterpenoids from Gingko biloba and many ethnobotanicals like Withania somnifera (L.) Dunal., Physostigma venenosum Balf., Bacopa monnieri (L.) Wettst., Centella asiatica (L.) Urb. have been used by traditional Indian, Chinese, and European system of medicines in AD. Clinical significance opioid alkaloid in Papaver somniferum has shown another dimension to this study. Over exploitation of medicinal plants with limited bioactive principles has provided templates to design synthetic drugs in AD e.g. rivastigmine, phenserine, eptastigmine based on chemical structure of physostigmine of Physostigma venenosum Balf. Even ZT-1 a prodrug of Hup A and memogain a prodrug of galantamine has achieved new direction in drug development in AD. All these first-line cholinesterase-inhibitors are used as symptomatic treatments in AD. Single modality of "One-molecule-one-target" strategy for treating AD has failed and so future therapies on "Combination-drugs-multi-targets" strategy (CDMT) will need to address multiple aspects to block the progression of pathogenesis of AD. Besides, cholinergic and amyloid drugs, in this article we summarize proteinopathy-based drugs as AD therapeutics from a variety of biological sources. In this review, an attempt has been made to elucidate the molecular mode of action of various plant products, and synthetic drugs investigated in various preclinical and clinical tests in AD. It also discusses current attempts to formulate a comprehensive CDMT strategy to counter complex pathogenesis in AD. MATERIALS AND METHODS: Information were collected from classical books on medicinal plants, pharmacopoeias and scientific databases like PubMed, Scopus, GoogleScholar, Web of Science and electronic searches were performed using Cochrane Library, Medline and EMBASE. Also published scientific literatures from Elsevier, Taylor and Francis, Springer, ACS, Wiley publishers and reports by government bodies and documentations were assessed. RESULTS: 60 no. of natural and synthetic drugs have been studied with their significant bioactivities. A decision matrix designed for evaluation of drugs for considering to the hypothetic "CDMT" strategy in AD. We have introduced the scoring pattern of individual drugs and based on scoring pattern, drugs that fall within the scoring range of 18-25 are considered in the proposed CDMT. It also highlights the importance of available natural products and in future those drugs may be considered in CDMT along with the qualified synthetic drugs. CONCLUSION: A successful validation of the CDMT strategy may open up a debate on health care reform to explore other possibilities of combination therapy. In doing so, it should focus on clinical and molecular relationships between AD and CDMT. A better understanding of these relationships could inform and impact future development of AD-directed treatment strategies. This strategy also involves in reducing costs in treatment phases which will be affordable to a common man suffering from AD.

[Pathogenesis of chronic disorders of cerebral circulation]. / Patogenez khronicheskikh rasstroistv mozgovogo krovoobrashcheniia.

Chronic disorders of cerebral circulation are a common syndrome, in the pathogenesis of which the important role play structural and functional alterations in large and small arteries, autoregulation of cerebral circulation and the level of systemic arterial pressure. Drugs that increase cerebral blood flow and restore the ability to its autoregulation are used, among others, in treatment of patients with CRMC. The possibility of using nicergoline (sermion) for the treatment of patients with CRMK is considered.

Changes in Regional Cerebral Perfusion after Nicergoline Treatment in Early Alzheimer's Disease: A Pilot Study.

BACKGROUND AND PURPOSE: Nicergoline is an ergoline derivative that is used to treat cognitive deficits in cerebrovascular disease and various forms of dementia. Although therapeutic effects of nicergoline have been established, little is known about its effects on cerebral perfusion in Alzheimer's disease (AD). The aim of this study was to examine the role of nicergoline in regional cerebral blood flow (rCBF) of AD patients using technetium-99m hexa-methyl-propylene-amine-oxime single photon emission computed tomography (SPECT). METHODS: Sixteen patients with early AD underwent a comprehensive clinical assessment including cognitive testing and SPECT scans before and after nicergoline treatment. Nicergoline (30 mg twice daily) was administered for an average duration of 1.5 years. Clinical and cognitive functioning was assessed using the Mini-Mental State Examination, Clinical Dementia Rating (CDR), CDR-Sum of Boxes, Global Deterioration Scale, Barthel Activities of Daily Living Index, Instrumental Activities of Daily Living, and Geriatric Depression Scale. RESULTS: Nicergoline treatment induced changes in the severity of dementia, cognitive function, activities of daily living, and depressive symptoms, which were not statistically significant. During the follow-up, the patients showed significant increases in their relative rCBF in the superior frontal gyrus, precentral gyrus, and postcentral gyrus. CONCLUSIONS: Nicergoline treatment improves perfusion of the frontal and parietal regions in early AD patients. It is possible that the increased perfusion in the superior frontal gyrus may be related to the mechanisms that delay or prevent progressive deterioration of cognitive functions in AD.

[Current approaches to optimize treatment of dementia and Alzheimer's disease]. / Sovremennye podkhody k optimizatsii terapii bolezni Al'tsgeimera.

Currently, substitution therapy is the main focus in the treatment of Alzheimer's disease (AD). It is aimed at overcoming neurotransmitter deficits in a variety of neuronal systems affected in AD. To overcome the cholinergic insufficiency, acetylcholinesterase inhibitors (rivastigmine, donepezil and galantamine) are primarily used. The efficacy and safety of these drugs in AD have been convincingly shown in numerous clinical trials in different countries. Memantine is the main drug in glutamatergic strategies in the treatment of AD, which has a neuroprotective effect and relieves symptoms at the level of the remaining glutamatergic synapses. Some other formulations (cerebrolysin, nicergoline etc) can be also applied as vasoactive and neuroprotective agents.