Insights into Pharmacological Potential of Apigenin through Various Pathways on a Nanoplatform in Multitude of Diseases.

Apigenin is a natural polyphenolic compound widely distributed as a glycoside in fruits and vegetables. Apigenin belongs to BCS class II with low solubility, which leads to poor absorption and bioavailability. It is mostly absorbed from the small intestine and extensively metabolized through glucuronidation and sulfation processes. Apigenin is known for its antioxidant and anti-inflammatory properties. It is also used as a chemopreventive drug in the management of various cancers. Pharmacological effects of apigenin have a wide range, from neuroprotective to treating renal disorders. Apigenin is non-toxic in nature and acts through various pathways (JAK/STAT, Wnt/ß-catenin, MAPK/ERK, PI3K/Akt, and NF-κB) to exert its therapeutic efficacy. Numerous formulations have been researched to enhance the bioavailability and pharmacological effects of apigenin. Combinatorial therapies are also researched to minimize the side-effects of chemotherapeutic drugs. The review presents pharmacokinetic and pharmacodynamic aspects of apigenin. Apigenin is safe for the treatment and management of numerous diseases. It can be easily incorporated into nanoformulation alone or in combination with other active ingredients to widen the therapeutic window. This review intends to help in drug optimization and therapeutic efficacy maximization for future studies.

Engineering of QbD driven and ultrasonically shaped lyotropic liquid crystalline nanoparticles for Apigenin in the management of skin cancer.

Treatment of skin cancer demands targeted delivery without minimal systemic circulation for maximum therapeutic window. Dermal delivery with nano-formulation offers such advantages. Therefore, present study aims to formulate Lyotropic liquid crystalline nanoparticles (LLC NPs) loaded with Apigenin (API) for dermal delivery using quality by design (QbD) approach for effective permeation resulting in improved bioavailability. Apigenin loaded LLC NPs (API-LLC NPs) were formulated and optimized by applying risk assessment and design of experiments (Box-Behnken Design). The optimized API-LLC NPs showed particle size, PdI and entrapment efficiency of 287.7 ± 9.53 nm, 0.152 ± 0.051 and 80 ± 2.2 % respectively. The optimized API-LLC NPs were characterized for morphology and crystallinity using optical microscopy, TEM, DSC and PXRD. In vitro and ex vivo studies showed sustained release and better permeation profile. CLSM study presented better penetration of API-LLC NPs which were quantitatively confirmed with dermatokinetics. Cytotoxic efficacy assessed on B16F10 cell lines showed a dose-dependent efficacy of API-LLC NPs with an IC50 of 45.74 ± 0.05. In a nutshell, the developed API-LLC NPs exhibit excellent potential for targeting deeper skin layers thereby can be considered a promising topical drug delivery nanocarrier in the treatment and management of skin cancer.

Effect of the MAGL/FAAH Dual Inhibitor JZL-195 on Streptozotocin-Induced Alzheimer's Disease-like Sporadic Dementia in Mice with an Emphasis on Aß, HSP-70, Neuroinflammation, and Oxidative Stress.

Alzheimer's disease is identified by pathological hallmarks such as intracellular neurofibrillary tangles (NFTs) and extracellular amyloid ß plaques. Several hypotheses exist to define the neurodegeneration including microglial activation associated with neuroinflammatory processes. Recently, pharmacological inhibition of endocannabinoid (eCB)-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), is being investigated to modulate the pathology of Alzheimer's disease. While MAGL inhibitors upregulate 2-acyl glycerol (2-AG) levels and reduce neuroinflammation, FAAH inhibitors elevate anandamide (AEA) levels and prevent the degradation of HSP-70, thereby preventing the phosphorylation of tau protein and formation of NFTs in neural cells. We investigated the possible neuroprotective potential of the dual MAGL/FAAH inhibitor JZL-195 (20 mg/kg) against ICV-STZ-induced sporadic Alzheimer's disease (SAD) in Swiss albino mice using donepezil (5 mg/kg) as the standard. The protective effects of JZL-195 were observed by the reversal of altered levels of Aß1-42, HSP-70, neuroinflammatory cytokines, and oxidative stress markers. However, JZL-195 expressed no cognitive improvement when assessed by spontaneous alternation behavior and Morris water maze tests and no effects on the AChE enzyme level in the hippocampal tissues of mice. Therefore, the findings of the present study indicate that although JZL-195 exhibited no improvement in cognitive deficits associated with sporadic Alzheimer's disease, it displayed significant reversal of the biochemical anomalies, thereby suggesting its therapeutic potential against the sporadic Alzheimer's disease model.

Roflumilast Reduces Pathological Symptoms of Sporadic Alzheimer's Disease in Rats Produced by Intracerebroventricular Streptozotocin by Inhibiting NF-κB/BACE-1 Mediated Aß Production in the Hippocampus and Activating the cAMP/BDNF Signalling Pathway.

Alzheimer's disease (AD) is a neurological disease that gradually causes memory loss and cognitive impairment. The intracellular secondary messenger cyclic nucleotide cAMP helps in memory acquisition and consolidation. In several models of AD, increasing their levels using phosphodiesterase (PDE) inhibitors improved cognitive performance and prevent memory loss. Thus, the current investigation was undertaken to investigate the therapeutic potential of the PDE-4 inhibitor roflumilast (RFM) against intracerebroventricular (ICV) streptozotocin (STZ)-induced sporadic AD in rats. STZ (3 mg/kg) was given to rats via the ICV route on the stereotaxic apparatus, followed by RFM (0.51 mg/kg/oral) treatment for 15 days, and donepezil (5 mg/kg/oral) was employed as a reference standard drug. Subsequently, we observed that RFM dramatically increased rats learning and memory capacities as measured by the Morris water maze and a novel object recognition task. RFM enhanced the levels of cAMP and brain-derived neurotrophic factors (BDNFs) while decreasing the expression of nuclear factor kappa B (NF-κB) and glial fibrillary acidic protein (GFAP) in the hippocampus of ICV-STZ-infused rats. RFM was found to significantly reduce ICV-STZ-induced neuroinflammation, amyloidogenesis, oxidative stress cholinergic impairments, GSK-3ß, and phosphorylated tau levels in the rat hippocampus. Supporting these, histopathological study using Cresyl violet and Congo red demonstrated that RFM reduced neuronal alterations and Aß deposition in the hippocampus of AD rats. These findings suggest that RFM could be a promising candidate for the management of AD by inhibiting NF-κB/BACE-1 mediated Aß production in the hippocampus and activating the cAMP/BDNF signalling pathway.

Comparative Study of Adverse Drug Reactions Associated with Filgrastim and Pegfilgrastim Using the EudraVigilance Database.

The primary prophylaxis with filgrastim (FIL) and pegfilgrastim (PEG-F) is recommended to decrease the severity of chemotherapy-induced neutropenia (CIN). The commonly reported adverse drug reactions (ADRs) with FIL and PEG-F is bone pain. ADRs pertaining to FIL and PEG-F were extracted from the European EudraVigilance (EV) database. The Individual Case Safety Reports (ICSRs) obtained from EV database that reported FIL and PEG-F as the suspected drug were analyzed. Registered ADRs (from the groups "General disorders and administration site conditions", "Blood and lymphatic system disorders", "Musculoskeletal and connective tissue disorders" and "Investigations") for FIL and PEG-F were collected from EV database from 2007 to 5 June 2021. The reporting odds ratio (ROR) was used to calculate ICSRs with most common ADRs related to FIL and PEG-F. A total of 17,403 ICSRs described the incidence of most common ADRs of FIL and PEG-F. The commonly reported ADRs for both drugs were pyrexia, bone pain, back pain, neutropenia and febrile neutropenia. The odds ratio of ICSRs belonging to the System Organ Class (SOC) "Investigations" (ROR 1.01 (CI 0.93-1.10)) revealed no significant difference in FIL and PEG-F. However, for the SOCs (General disorders and administration site conditions" and "Musculoskeletal and connective tissue disorders" ((ROR 1.14 (CI 1.06-1.21); ROR 1.21 (CI 1.18-1.32), respectively), an increased reporting probability with PEG-F was found. The authors reported a lower reporting probability for the SOC "Blood and lymphatic system disorders" for FIL versus PEG-F (ROR 0.75 (CI 0.70-0.80)). Our results have demonstrated that the occurrence of bone pain was similar with FIL and PEG-F. For the incidence of pyrexia and back pain, PEG-F was associated with a higher reporting probability as compared to FIL. However, the incidence of neutropenia and febrile neutropenia was higher in FIL compared to PEG-F. Further evaluation of data from real life is needed.

Linagliptin, a DPP-4 inhibitor, ameliorates Aß (1-42) peptides induced neurodegeneration and brain insulin resistance (BIR) via insulin receptor substrate-1 (IRS-1) in rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the most devastating neurodegenerative disorder, accounting over 46 million cases of dementia globally. Evidence supports that Brain Insulin Resistance (BIR) due to serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1) has an association with AD. GLP-1 an incretin hormone, rapidly degraded by Dipeptidyl Peptidase-4 (DPP-4) has also confirmed its efficacious role in AD. Linagliptin, a DPP-4 inhibitor is hypothesized to increase GLP-1 level, which then crosses Blood Brain Barrier (BBB), decreases Amyloid-beta (Aß) and insulin resistance in hippocampus. Thus, the present study was designed to evaluate Linagliptin in Aß (1-42) peptides induced rat model of AD. Following 1 week of induction, rats were administered with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) orally for 8 weeks and donepezil (5 mg/kg) as a reference standard. At the end of scheduled treatment neurobehavioral parameters were assessed. After this, rats were sacrificed, hippocampus was isolated from the whole brain for histopathological analysis and biochemical parameters estimation. Linagliptin dose-dependently and significantly reversed motor and cognitive impairment, assessed through locomotor activity (LA) and Morris water maze (MWM) test respectively. Moreover, Linagliptin augmented GLP-1 level and attenuated soluble Aß (1-42), IRS-1 (s307), GSK-3ß, TNF-α, IL-1ß, IL-6, AchE and oxidative/nitrosative stress level in hippocampus. H&E and Congo red staining also exhibited neuroprotective and anti-amylodogenic effect respectively. Our study findings implies the significant effect of Linagliptin in reversing the behavioural and biochemical deficits by altering Aß (1-42) and BIR via IRS-1 confirming one of the mechanism underlying the pathophysiology of AD.

Roflumilast and tadalafil improve learning and memory deficits in intracerebroventricular Aß1-42 rat model of Alzheimer's disease through modulations of hippocampal cAMP/cGMP/BDNF signaling pathway.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent age-dependent neurodegenerative disease characterized by progressive impairment of memory and cognitive functions. Cyclic nucleotides like cAMP and cGMP are well-known to play an important role in learning and memory functions. Enhancement of cAMP and cGMP levels in the hippocampus by phosphodiesterase (PDE) inhibitors might be a novel therapeutic approach for AD. Thus, the present study was planned to explore the therapeutic potential of roflumilast (RFM) and tadalafil (TDF) phosphodiesterase inhibitors in intracerebroventricular (ICV) Aß1-42 induced AD in rats. METHODS: ICV Aß1-42 was administered in rats followed by treatment with RFM (0.05 mg/kg) and TDF (0.51 mg/kg) for 15 days. Novel object recognition (NOR), and Morris water maze (MWM) test were performed during the drug treatment schedule. On the day, 22 rats were sacrificed, and hippocampus was separated for biochemical, neuroinflammation, and histopathological analysis. RESULTS: Aß1-42 infused rats were induce behavioral impairment and increased AChE, BACE-1, Aß1-42, GSK-3ß, phosphorylated tau (p-Tau), pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) levels, oxidative stress (increased MDA, Nitrite and decreased GSH), histopathological changes, and reduced cAMP, cGMP, and BDNF levels. RFM and TDF significantly attenuated Aß1-42 induced memory deficits and neuropathological alterations in the hippocampus. CONCLUSION: The outcomes of the current study indicate that RFM and TDF lead to memory enhancement through upregulation of cAMP/cGMP/BDNF pathway, thus they may have a therapeutic potential in cognitive deficits associated with AD.

Alendronate reduces the cognitive and neurological disturbances induced by combined doses of d-galactose and aluminum chloride in mice.

Neurological disturbances including cholinergic dysfunction, oxidative stress, neuroinflammation, and cognitive impairments are the well-reported consequences of old age-related disorders like Alzheimer's disease (AD) or dementia. Bisphosphonates were shown to ameliorate dementia in osteoporotic patients, neuroinflammation, and cholinesterase activity in rodents. Thus, the present study has been designed to examine the role of alendronate against cognitive and neurological disturbances in mice induced by a combined oral dose of d-galactose and aluminum chloride (AlCl3 ) for 6 weeks. d-galactose acts as a senescence agent, whereas AlCl3 is a neurotoxin and in combination generates neuropathologies and cognitive depletion resembling aging and AD. It was found that memory was markedly impaired in d-galactose + AlCl3 -treated mice as assessed in different behavioral paradigms. Additionally, d-galactose + AlCl3 led to neurotoxicity assessed on the basis of neuroinflammation, oxidative stress, glial cell activation, neuronal damage, and augmented GSK-3ß level in mice hippocampus. Consequently, alendronate administration orally for 15 days in d-galactose + AlCl3 -exposed mice prominently reversed all these behavioral and neuropathological changes. These findings show that alendronate can be a potential therapeutic molecule with multiple targets for the management of age-related neurological disorders such as AD.

Development, optimisation and evaluation of chitosan nanoparticles of alendronate against Alzheimer's disease in intracerebroventricular streptozotocin model for brain delivery.

The current study aimed to develop alendronate (ALN)-loaded chitosan nanoparticles (CS-ALN-NPs) for brain delivery via intranasal route. These CS-ALN-NPs reduced the peripheral side effects and released ALN directly to brain. These NPs were formulated through ionic gelation technique by mixing sodium tripolyphosphate (1.5 mg/ml) in ALN-CS (1.75 mg/ml) solution. CS-ALN-NPs attained 135.75 ± 5.80 nm, 0.21 ± 0.013, 23.8 ± 3.69 mV, 72.46 ± 0.879% and 30.92 ± 0.375% mean particle size, PDI, zeta potential, entrapment efficiency and loading capacity, respectively. Furthermore, the TEM and SEM analysis of CS-ALN-NPs, respectively, revealed the particle size in 200 nm range and spherical shape. The in vitro and ex vivo release profile revealed a sustained drug release through CS-ALN-NPs as compared to pure drug solution. Also these NPs acquired a high concentration in mice brain and better pharmacokinetic profile than ALN solution (intranasal) CS-ALN-NPs were then evaluated against intracerebroventricular-streptozotocin (ICV-STZ) induced Alzheimer's disease (AD)-like pathologies in mice. The intranasal CS-ALN-NP altered the ICV-STZ induced neurobehavioral, neurochemical and histopathological changes in mice. These effects were significant to those of ALN solution (intranasal). The neuroprotective potential of CS-ALN-NPs observed in ICV-STZ mice model of AD may be a promising brain-targeted delivery system for AD treatment along with further extensive exploration at both pre-clinical and clinical edge. HIGHLIGHTS CS-ALN-NPs were developed and optimised to overcome the poor pharmacokinetic profile and associated side effects of ALN CS-ALN-NPs showed particle size within 200 nm range as well as controlled and sustained release in in vitro release study These optimised NPs of ALN attained higher brain:blood ratio and better pharmacokinetic profile (Cmax, tmax, AUC) CS-ALN-NPs markedly altered ICV STZ induced impairment in cognitive functions of mice and changes in APP processing, neuroinflammatory cytokines and other biochemical parameters in mice hippocampus.

Neuroprotective role of alendronate against APP processing and neuroinflammation in mice fed a high fat diet.

Obesity and consumption of diet rich in fat are known to contribute to the development of Alzheimer's disease (AD) which is a complex and multifactorial neurodegenerative disease and a leading cause of mortality with unmet medical needs. Hypercholesterolemia was discovered to increase neuropathological changes along with cognitive decline in AD mouse models but still the underlying mechanism is elusive. Furthermore, isoprenoids, the crucial products of Mevalonate-pathway produced by the action of farnesyl pyrophosphate synthase (FPPS) enzyme, are also demonstrated to play a key role in AD. Nevertheless, bisphosphonates target this enzyme in order to treat osteoporosis and also found to alleviate dementia in such patients. As per the cited inhibitory action of alendronate, against acetylcholinesterase and cholesterol level, we hypothesized to explore the potential of alendronate against high fat diet (HFD) induced neuropathologies and cognitive disabilities in AD mouse model. Here we noticed that in mice provided with HFD for 14 weeks, spatial memory was compromised as interpreted in different behavioral paradigms. Together with cognitive depletion, there was observed a provoking effect on amyloid precursor protein (APP)-processing via amyloidogenic pathway due to enhanced ß-site APP cleaving enzyme-1 (BACE-1) level which in turn leads to augmented release of amyloid beta (Aß) in hippocampus of HFD mice. Relevant to these, significant elevation in hippocampal level of neuroinflammatory cytokines, oxidative stress markers and isoprenoids and serum cholesterol were also found after HFD exposure. Marked reversal of cognitive impairment, enhanced APP-processing, neuroinflammation along with other neuropathological alterations in hippocampus was demonstrated following oral administration of alendronate (1.76 mg/kg) for 15 days despite of HFD treatment. These changes were noted to be due to modulation of isoprenoids and cholesterol level by alendronate. Supporting these, histopathological analysis done by congo red revealed the reduced Aß deposition in hippocampus of drug treated HFD mice The current outcomes provide important implications for the contribution of Mevalonate-pathway and HFD for the onset of AD and also support alendronate as a prominent intervention for amelioration of AD-like pathologies.

Thymoquinone Loaded Solid Lipid Nanoparticles Demonstrated Antidepressant-Like Activity in Rats via Indoleamine 2, 3- Dioxygenase Pathway.

The World Health Organization (WHO) has ranked depression the 4th leading cause of disability worldwide. Thymoquinone (TQ), is an active constituent of Nigella sativa having various medicinal properties but has poor solubility and bioavailability. This problem was overcome by developing nanoformulation of TQ. Previously TQ reported good antioxidant and anti-inflammatory effects. Recently TQ's anti-depressant effect was demonstrated. However, the mechanisms underlying the antidepressant effect of TQ still needs evaluation. Activation of Indoleamine-2,3-dioxygenase (IDO), (an enzyme that participates in the tryptophan metabolism), leads to a decrease of serotonin (5-HT) levels. The expression of this enzyme is associated with immune system activation, which has been proposed as a common mechanism that links depression. The present study was performed in stressed animals where hippocampal levels of pro-inflammatory cytokines (IL-6 and TNF α levels), brain derived neurotropic factor (BDNF) and hippocampal kynurenine (KYN), tryptophan (TRP) and serotonin (5-HT) levels were estimated. Treatment with TQ solid lipid nanoparticles (TQSLN 20 mg/kg p.o) and TQ suspension (20 mg/kg p.o) demonstrated antidepressant-like activity in chronic forced-swim stress model. Further, it reduced the elevated hippocampal IL-6 & TNFα and reversed the increased activity of IDO as measured by ratio of hippocampal KYN/TRP and 5HT/TRP in stressed rats. The results of the present study confirm anti-inflammatory and neuroprotective effects of TQ which may be associated with 5-HT pathway. Thus, the present study offers a newer approach to reduce symptoms of depression using TQSLN. Our results are preliminary, further research is needed for more conclusive view.

No association between proton pump inhibitor use and risk of dementia: Evidence from a meta-analysis.

BACKGROUND AND AIM: A growing body of literature suggests the association between dementia risk and proton pump inhibitor (PPI) use. Therefore, we aimed to investigate the association between PPI use and dementia risk. METHODS: An extensive literature search was performed in PubMed, Embase, and Cochrane till March 31, 2019. All the studies (cohort and case-control) assessing the association between PPI use and dementia risk were eligible for inclusion. Articles were selected based on the screening of title and abstract, data were extracted, and risk of bias was assessed using Newcastle-Ottawa scale. The primary outcome was pooled risk of dementia among PPI user as compared with non-PPI user. Secondary outcomes include dementia risk based on subgroups. Statistical analysis was performed using review manager software. RESULTS: Twelve studies (eight cohort and four case-control) were found to be eligible for inclusion. Majority of the studies were of high quality. Dementia was diagnosed based on International Classification of Diseases 9/10 codes in majority of the included studies. PPI use was not associated with the dementia risk, with a pooled relative risk (RR) of 1.05 (95% confidence interval [CI]: 0.96-1.15), P = 0.31. Subgroup analysis based on study design (cohort: P = 0.14; case-control: P = 0.14), sex (RR 1.25 [95% CI: 0.97-1.60], P = 0.08), histamine 2 receptor antagonist blockers (P = 0.93), and Alzheimer's disease (RR 1.00 [95% CI: 0.91-1.09], P = 0.93) revealed no significant association between PPI use and dementia risk. CONCLUSION: We found no significant association between PPI use and the risk of dementia or Alzheimer's disease.

Effect of lacosamide on ethanol induced conditioned place preference and withdrawal associated behavior in mice: Possible contribution of hippocampal CRMP-2.

BACKGROUND: Excessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice. METHODS: The behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured. RESULTS: Ethanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice. CONCLUSION: The present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.

Exploring the multifaceted neuroprotective actions of Emblica officinalis (Amla): a review.

Today, neurological disorders such as epilepsy, depression, tardive dyskinesia, and stress, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, dementia, and Huntington's disease affect millions of people all over the world. Existing pharmacological interventions do not meet the desired therapeutic benefits for a significant number of patients, and hence, numerous research studies are in progress to find novel therapies for these disorders. Herbal drugs, which have been used in traditional medicine for centuries, are also being explored and scientifically evaluated for the treatment of these neurological disorders. While substantial evidence exists for the antioxidant, anti-inflammatory, anti-hyperlipidemic, and anti-hyperglycemic effects of Emblica officinalis, in vivo and in vitro studies, have also revealed its beneficial therapeutic activities in numerous neurological disorders. These diverse neuroprotective pharmacodynamic actions of E. officinalis corroborated by accumulating evidence in pre-clinical research studies deserve the attention of the scientific community to develop viable pharmacotherapeutic strategies. The present review elaborates upon the latest scientific evidence pertaining to the pharmacological effects of E. officinalis in numerous neurological and neurodegenerative disorders and also gives way for future research in this area.

Behavioral Experimental Paradigms for the Evaluation of Drug's Influence on Cognitive Functions: Interpretation of Associative, Spatial/Nonspatial and Working Memory.

BACKGROUND: Currently, a large number of people throughout the world are affected by neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease which appear with a lapse in recall, attention and altered cognitive functions. Learning and memory, the fundamental indices defining cognitive functions, are the complex psychological processes governing acquisition, consolidation, and retrieval of stored information. These processes are synchronized by the coordination of various parts of the brain including hippocampus, striatum and amygdala. OBJECTIVE: The present review is centered on different behavioral paradigms in rodents interpreting learning and memory both explicitly and implicitly. Furthermore, it is also emphasizing on the interaction of various brain structures during different stages of associative, spatial and non-spatial memory. METHODS: We embarked on an objective review of literature relevant to screening methods for evaluation of drug's influence on a wide range of cognitive functions (learning and memory) as well as the underlying mechanism responsible for modulation of these functions. RESULTS: Our review highlighted the behavioral paradigms based on associative, spatial/nonspatial and working memory. The cited research acknowledged the hippocampal and striatal control on learning and memory. CONCLUSION: Since the neurodegenerative disorders and dementia have continuously been increasing, a wide range of therapeutic targets have been developed at the cellular and molecular level. This arises the necessity of screening of these targets in different cognitive behavioral paradigms which reflect their memory enhancing potential. The understanding of behavioral models and the involvement of brain structures in cognitive functions highlighted in the present review might be helpful to advance therapeutic interventions.

Ameliorative effect of alendronate against intracerebroventricular streptozotocin induced alteration in neurobehavioral, neuroinflammation and biochemical parameters with emphasis on Aß and BACE-1.

Alzheimer's disease (AD) is the most prevalent age related neurodegenerative disorder manifested by progressive cognitive decline and neuronal loss in the brain, yet precise etiopathology of majority of sporadic or late-onset AD cases is unknown. AD is associated with various pathological events such as Aß deposition due to BACE-1 induced cleavage of APP, neuroinflammation, increased cholesterol synthesis, cholinergic deficit and oxidative stress. It was found that bone drug, alendronate (ALN) that cross blood brain barrier inhibits brain cholesterol synthesis and AChE enzyme activity. As cholesterol modifying agents have been supposed to alter AD like pathologies, the current study was designed to investigate the possible neuroprotective and therapeutic potential of ALN against ICV STZ induced experimental sporadic AD (SAD) in mice in a non-cholesterol dependent manner, using donepezil (5 mg/kg) as a reference standard. The preliminary study was done by molecular modelling to identify the binding affinity of ALN with BACE-1 in silico. The prevention of cognitive impairment in mice induced by ICV STZ (3 mg/kg) infused on first and third day, by ALN (1.76 mg/kg p.o.) administered for 15 consecutive days was assessed through Spontaneous Alternation Behavior (SAB) and Morris water maze (MWM) test. Additionally, the protective effect of ALN was also observed by the reversal of altered levels of Aß1-42, BACE-,1 neuroinflammatory cytokines, AChE activity and oxidative stress markers (except TBARS) in ICV-STZ infused mice. However, the findings of the present study imply the therapeutic potential of ALN against SAD-like complications.

Bisphosphonates: Future perspective for neurological disorders.

Neurodegenerative disorders and osteoporosis share some common underlying pathological features including calcium overload, accumulation of toxic chemicals, inflammation and impaired protein prenylation by isoprenoids (farnesyl pyrophosphate and geranylgeranyl pyrophosphate) appear later stage of life. Substantial number of pre-clinical and clinical reports as well as in vitro data univocally acknowledged the negative impact of altered post-translational modification (prenylation) of proteins like small GTPases (Rffhes, Rho, Rac etc.) and cholesterol levels in both serum and brain on CNS integrity. Bisphosphonates (BPs), referred to as gold standard for osteoporosis treatment, have well established role in attenuation of bone resorption and osteoclast apoptosis by inhibition of farnesyl pyrophosphate synthase enzyme (FPPS) in mevalonate pathway. BPs mainly nitrogen containing BPs (NBPs) have potential to offer new therapeutic targets for neurological disorders and received increasing attention in recent years. A year back clinical and pre-clinical studies revealed that NBPs have the potential to alleviate the symptoms of neurological disorders like brain calcification, Alzheimer's disease and Huntington's disease by targeting mevalonate pathway. Though these drugs have well developed role in inhibition of isoprenoids synthesis, these were demonstrated to inhibit acetyl cholinesterase enzyme and cholesterol synthesis in brain that are considered as the critical factors for impairment of cognitive functions which is the hallmark of several neurological disorders. Still the current understanding of BPs' effect in CNS is limited due to lack of studies focusing the molecular and cellular mechanism. The present review aims to reveal the updated discussion on the mechanism contributing BPs' effect in CNS disorders.