Therapeutic Potential of Capsaicin in various Neurodegenerative Diseases with Special Focus on Nrf2 Signaling.

Neurodegenerative disease is mainly characterized by the accumulation of misfolded proteins, contributing to mitochondrial impairments, increased production of proinflammatory cytokines and reactive oxygen species, and neuroinflammation resulting in synaptic loss and neuronal loss. These pathophysiological factors are a serious concern in the treatment of neurodegenerative diseases. Based on the symptoms of various neurodegenerative diseases, different treatments are available, but they have serious side effects and fail in clinical trials, too. Therefore, treatments for neurodegenerative diseases are still a challenge at present. Thus, it is important to study an alternative option. Capsaicin is a naturally occurring alkaloid found in capsicum. Besides the TRPV1 receptor activator in nociception, capsaicin showed a protective effect in brain-related disorders. Capsaicin also reduces the aggregation of misfolded proteins, improves mitochondrial function, and decreases ROS generation. Its antioxidant role is due to increased expression of an nrf2-mediated signaling pathway. Nrf2 is a nuclear erythroid 2-related factor, a transcription factor, which has a crucial role in maintaining the normal function of mitochondria and the cellular defense system against oxidative stress. Intriguingly, Nrf2 mediated pathway improved the upregulation of antioxidant genes and inhibition of microglial-induced inflammation, improved mitochondrial resilience and functions, leading to decreased ROS in neurodegenerative conditions, suggesting that Nrf2 activation could be a better therapeutic approach to target pathophysiology of neurodegenerative disease. Therefore, the present review has evaluated the potential role of capsaicin as a pharmacological agent for the treatment and management of various neurodegenerative diseases via the Nrf2-mediated signaling pathway.

Bilayer fixed-dose combination tablet for curcumin microparticles and piroxicam and in vitro evaluation.

Aim: In the present work, fixed-dose combination of bilayer tablets for piroxicam as and curcumin as immediate-release and sustained-release layer (SRL) respectively for management of inflammatory response. Materials & methods: The SRL include Curcumin polycaprolactone microparticles from spray drying. The tablet layers include Pearlitol 200SD, Microcrystalline cellulose PH101, Aerosil 200, talc each layer. Results: SEM studies confirm spherical microparticles. PXRD and DSC studies confirm the amorphous microparticles. In vitro studies exhibit, an immediate release and sustained release for Piroxicam and Curcumin after 2 h. Cellular uptake studies on RAW 264.7 cells confirm the complete internalization of microparticles. Conclusion: Therefore, it was concluded that microparticles can be formulated into a unit dosage form for the management of inflammation.

Transferrin decorated PLGA encumbered moxifloxacin nanoparticles and in vitro cellular studies.

PURPOSE: Complicated intra-abdominal infection (cIAI) management involves administering antibiotics that destroy the cell wall and the genesis of bacterial lipopolysaccharide (LPS). During the infectious state, the expression of transferrin receptors upregulates on the intestinal epithelial cells, which are considered the site of infection. In the present research, transferrin decorated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) encapsulated moxifloxacin (MOX) were developed for possible targeting of the receptors in the colon. SIGNIFICANCE: This study will explore more about the incorporation of transferrin as effective coating material in targeted drug delivery. METHODS: Nanoparticles were prepared using nano-emulsification and surface modification with transferrin was done by layer-by-layer methodology and evaluated by powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), FTIR, SEM, antibacterial activity, and cellular uptake studies. RESULTS: The formulated NPs exhibit a size of ≈170 nm, PDI ≈ 0.25, zeta potential ≈-4.0 mV, drug loading ≈ 6.8%, and entrapment efficiency of 82%. Transferrin-decorated NPs exhibit tailored release for almost 12 h and in vitro antibacterial activity for 14 h. The cellular uptake studies were done on a RAW264.7 cell line for better determination of transferrin uptake of fabricated NPs. CONCLUSION: The above study circumvents around the preparation of transferrin decorated PLGA encumbered MOX NPs intended for cIAI-induced sepsis. PLGA NPs provide tailored release of MOX with primary burst and followed by sustained release. These observations confines with antibacterial activity studies. The prepared transferrin-coated NPs were stable and effectively uptaken by RAW264.7 cells. However, future studies include the preclinical investigation of these NPs in sepsis-induced murine models.

A Comprehensive Review on Preclinical Evidence-based Neuroprotective Potential of Bacopa monnieri against Parkinson's Disease.

Parkinson's disease is a chronic and gradually progressive neurodegenerative disorder triggered due to the loss of dopamine-releasing neurons in the region of substantia nigra pars compacta characterized by the motor symptoms, such as tremor, bradykinesia, akinesia, and postural instability. Proteinopathies, mitochondrial dysfunction induced dopaminergic neuronal deterioration, and gene mutations are the hallmarks of Parkinson's disease. The bioactive components of Brahmi, such as Bacoside A, Bacoside B, and Bacosaponins, belong to various chemical families. Brahmi's neuroprotective role includes reducing neuronal oxidative stress, dopaminergic neuronal degeneration, mitochondrial dysfunction, inflammation, inhibition of α-synuclein aggregation, and improvement of cognitive and learning behaviour. Researchers found that Bacopa monnieri significantly increased brain levels of glutathione, vitamin C, vitamin E, and vitamin A in rats exposed to cigarette smoke. Brahmi has a potent antioxidant property and neuroprotective effects against PD that help reduce oxidative stress and neuroinflammation and enhance dopamine levels. The review collates all the preclinical studies that prove the beneficial neuroprotective effect of Brahmi for treating PD.

Bacopa monnieri attenuates glutamate-induced nociception and brain mitochondrial toxicity in Zebrafish.

Bacopa monnieri L. (BM; Family: Scrophulariaceae), commonly known as Brahmi, is traditionally used as a nootropic agent. BM also exhibits significant analgesic activity in experimental models of pain. However, the effect of Bacopa monnieri against glutamate-induced nociception in zebrafish is yet to be explored in experimental condition. Therefore, the present study was designed to evaluate the effect of BM against glutamate-induced nociception and brain mitochondrial toxicity in adult zebrafish (Danio rerio). BM at 0.625, 1.25 and 2.5 mg/ml was administered to adult zebrafish and after half an hour glutamate was injected through i.m. route of administration. Indomethacin was used as standard drug. After behavioral analysis, the fish were euthanized and the brain was isolated and stored for further biochemical analysis. BM (1.25 and 2.5 mg/ml) and indomethacin significantly attenuated the glutamate-induced increase in number of line crossing compared to control group animals. Additionally, BM (1.25 and 2.5 mg/ml) and indomethacin significantly reduced the glutamate induced increase in cytosolic calcium level. Further, there was a substantial improvement in mitochondrial function, integrity and bioenergetics in term of respiratory control rate and ADP/O in zebrafish brain. Moreover, BM (1.25 and 2.5 mg/ml) and indomethacin significantly reduced the glutamate-induced mitochondria-dependent apoptosis in zebrafish brain. Therefore, BM could be a potential alternative drug candidate in the management of pain.

Antinociceptive activity of standardized extract of Bacopa monnieri in different pain models of zebrafish.

ETHNOPHARMACOLOGICAL RELEVANCE: Bacopa monnieri L. (Scrophulariaceae) is commonly known as Brahmi and traditionally used as a neuroprotective herbal medicine. Recently, Bacopa monnieri exhibited significant therapeutic activity against animal model of neuropathic pain. However, the therapeutic potential of methanolic extract of Bacopa monnieri in experimental animal model is yet to establish. AIM OF THE STUDY: The present study was designed to evaluate the anti-nociceptive potential of standardized methanolic extract of Bacopa monnieri in experimental adult zebrafish (Danio rerio) model of pain. MATERIALS AND METHODS: The methanolic extract of Bacopa monnieri (BME) was standardized to bacoside-A using chromatographic method. Subsequently, BME (0.75, 1.25 and 5.0 mg/ml) was evaluated for anti-nociceptive activity using adult zebrafish model. RESULTS: Standardized BME showed antioxidant effect through radical quenching activity in in vitro study. BME at 1.25 mg/ml significantly decreased the nociceptive effect induced by different noxious agents like acetic acid where as BME at 2.5 mg/ml exhibited significant antinociceptive activity against glutamate, formalin, capsaicin, cinnamaldehyde when compared to control and sham group animals. CONCLUSION: BME exerted antinociceptive activity in adult zebrafish. It could be presumed that BME may involve glutamatergic receptor, ASIC and TRP channel activity in its anti-nociceptive effect. BME could be considered as a potential therapeutic option in the management of pain.

Role of caveolin-eNOS platform and mitochondrial ATP-sensitive potassium channel in abrogated cardioprotective effect of ischemic preconditioning in postmenopausal women

Abstract Caveolin, the protein of the caveolar membrane, interacts and binds with endothelial nitric oxide synthase (eNOS), forming a caveolin-eNOS complex leading to suppression of the eNOS activity. Caveolin, therefore, maintains eNOS in the inactivated state leading to reduced nitric oxide (NO) production. Ischemic preconditioning disrupts the caveolin-eNOS complex leading to activation of the eNOS and thus results in cardioprotection. During ischemic preconditioning, NO produces cardioprotection by the opening of the KATP channel, and the caveolin forms a suitable signalling platform facilitating the interaction of NO with the KATP channel. Estrogen deficiency has been reported to upregulate caveolin-1 expression. The article aims to review the various mechanisms that placed the women at the risk of coronary artery diseases after postmenopausal estrogen deficiency and their role in the cardioprotective effect of ischemic preconditioning.

Quercetin Exhibits α7nAChR/Nrf2/HO-1-Mediated Neuroprotection Against STZ-Induced Mitochondrial Toxicity and Cognitive Impairments in Experimental Rodents.

The objective of the present study was to investigate the α7nAChR-mediated Nrf2-dependant protective activity against streptozotocin (STZ)-induced brain mitochondrial toxicity in Alzheimer's disease (AD)-like rats. STZ (3 mg/kg) was injected through an intracerebroventricular route to induce AD-like dementia. Repeated Quercetin (50 mg/kg, i.p.) administration attenuated cognitive impairments in the STZ-challenged animals during Morris water-maze and Y-maze tests. Quercetin significantly mitigated the STZ-induced increase in cholinergic dysfunction, such as the increase in acetylcholinesterase activity, decrease in acetylcholine level, and activity of choline acetyltransferase, and increase in amyloid-beta aggregation and mitochondrial toxicity in respect of mitochondrial bioenergetics, integrity, and oxidative stress in memory-challenged rat hippocampus, prefrontal cortex and, amygdala. Further, Quercetin significantly attenuated STZ-induced reduction in the α7nAChRs and HO-1 expression levels in the selected rat brain regions. On the contrary, trigonelline (10 mg/kg, i.p.) and methyllycaconitine (2 mg/kg; i.p.) abolished the neuroprotective effects of Quercetin against STZ-induced behavioral, molecular, and biochemical alterations in the AD-like animals. Hence, Quercetin exhibits α7nAChR/Nrf2/HO-1-mediated neuroprotection against STZ-challenged AD-like animals. Thus, Quercetin could be considered as a potential therapeutic option in the management of AD.

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 (Aß)-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 Aß-induced neurotoxicity. The experimental dementia was induced in the male rats by intracerebroventricular administration of Aß(1-42) on day-1 (D-1) of the experimental schedule of 14 days. Ang(1-7) was administered once daily from D-1 toD-14 to the Aß-challenged rodents. Ang(1-7) attenuated Aß-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 Aß-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 Aß in rat hippocampus, pre-frontal cortex and amygdala. Furthermore, Ang(1-7) reversed Aß-induced decrease in the mitochondrial function, integrity and bioenergetics in all brain regions. Additionally, Ang(1-7) attenuated Aß-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 Aß-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.

Naringin Exhibits Mas Receptor-Mediated Neuroprotection Against Amyloid Beta-Induced Cognitive Deficits and Mitochondrial Toxicity in Rat Brain.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with clinical manifestation of loss in cognitive functions in an individual. Though several drug candidates have been developed in the management of AD, an alternative option is still required due to serious adverse effects of the former. Recently, naringin exerts therapeutic benefits through rennin angiotensin system in experimental animals. However, its report  on Mas receptor-mediated action against amyloid beta (Aß)-induced mitochondrial dysfunction in AD-like animals is lacking. The experimental dementia was induced in the male rats by intracerebroventricular administration of Aß(1-42) on day 1 (D-1) of the experimental schedule of 14 days. Naringin treatment for 14 days attenuated Aß-induced cognitive impairments of the animals in Morris water maze (MWM) and Y-maze tests. Further, naringin ameliorated the Aß-induced cholinergic dysfunction in terms of decrease in the activity of choline acetyl transferase (ChAT) and level of acetylcholine (ACh) and increase in the activity of acetylcholine esterase (AChE) in rat hippocampus, prefrontal cortex, and amygdala. Furthermore, naringin attenuated Aß-induced decrease in mitochondrial function, integrity, and bioenergetics in all the brain regions. Naringin also attenuated Aß-induced increase in mitochondrial and cytosolic calcium level in all the brain regions. Moreover, naringin reversed Aß-induced increase in apoptosis and level of mitochondrial calcium uniporter and decrease in the level of hemeoxygenase-1 in all the brain regions. On the contrary, A779 significantly abolished the therapeutic potential of naringin on Aß-induced alteration in behavioral, biochemical, and molecular observations in these experimental animals. Thus, these observations indicate that naringin could be potential alternative in the management of AD.

Ang (1-7)/Mas receptor-axis activation promotes amyloid beta-induced altered mitochondrial bioenergetics in discrete brain regions of Alzheimer's disease-like rats.

Renin Angiotensin System plays significant role in the memory acquisition and consolidation apart from its hemodynamic function in the pathophysiology of Alzheimer's disease (AD). It has been reported that Ang (1-7) ameliorates the cognitive impairment in experimental animals. However, the effect of Ang (1-7)/Mas receptor signaling is yet to be explored in Aß42-induced memory impairment. Aß42 was intracerebroventricularly injected into the male rats on day-1 (D-1) of the experimental schedule of 14 days. All the drugs were administered from D-1 to D-14 in the study design. Aß42 significantly increased the escape latency during Morris water maze (MWM) test on D-10 to13 in the animals. Further, Aß42 significantly decreased the time spent and percentage of total distance travelled in the target quadrant of the rats on D-14 in the MWM test. Aß42 also significantly decreased the spontaneous alteration behavior on D-14 during Y-maze test. Moreover, there was a significant increase in the level of Aß42, decrease in the cholinergic function (in terms of decreased acetylcholine and activity of cholinesterase, and increased activity of acetylcholinesterase), mitochondrial function, integrity and bioenergetics, and apoptosis in all the rat brain regions. Further, Aß42 significantly decreased the level of expression of heme oxygenase-1 in all the rat brain regions. Ang (1-7) attenuated Aß42-induced changes in the behavioral, biochemical and molecular observations in all the selected rat brain regions. However, A779, Mas receptor blocker, significantly abolished the beneficial effects of Ang (1-7) in Aß42-induced cognitive deficit animals. These observations clearly indicate that the Ang (1-7)/Mas receptor activation could be a potential alternative option in the management of AD.

Manilkara hexandra (Roxb.) Dubard Ameliorates Acetic Acid-induced Rat Gastric Ulcer.

Manilkara hexandra (Roxb; Family:sapotaceae) is reported to exert preventive effect in several experimental ulcer models. However, there is no report of M. hexandra on gastric ulcer healing property. Thus, the present study was designed to evaluate the gastric ulcer healing activity of methanolic stem bark extract of M. hexandra (MH) and to derive a plausible molecular level of mechanism of action. MH was subjected to several phytochemical screening tests and standardized to quercetin by HPTLC. In the first pharmacological experiment, the standardized MH (50, 100 and 200 mg/kg) was carried out for ulcer healing activity against acetic acid (AA)-induced gastric ulcer in male rats. MH (100 and 200 mg/kg) ameliorated AA-induced rat gastric lesions. Further, MH (100 and 200 mg/kg) attenuated AA-induced changes in the levels of lipid peroxidation (LPO), reduced glutathione (GSH), oxidized glutathione (GSSG) and ratio of GSH/GSSG and activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) enzymes, and level of hame oxygenase-1 (HO-1) in stomach tissue. In the subsequent set of experiment, trigonelline (30 mg/kg; p.o.), a potent Nrf2 antagonist, significantly abrogated the gastric ulcer healing activity of MH (100 mg/kg) in AA challenged animals. Further, trigonelline attenuated the effects of MH (100 mg/kg) on the levels of LPO, GSH, GSSG and ratio of GSH/GSSG and activity of SOD, CAT, GPx and GR enzymes, and level of HO-1 in AA challenged rodents. These observations implicate the fact that MH could be a better therapeutic alternative in the management of gastric ulcer.

5-N-ethyl Carboxamidoadenosine Stimulates Adenosine-2b Receptor-Mediated Mitogen-Activated Protein Kinase Pathway to Improve Brain Mitochondrial Function in Amyloid Beta-Induced Cognitive Deficit Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss in memory as one of the cardinal features. 5-N-ethyl carboxamidoadenosine (NECA), an agonist of adenosine-2b receptor, exerts neuroprotective activity against several experimental conditions. Further, NECA activates mitogen-activated protein kinase (MAPK) and also attenuates mitochondrial toxicity in mammalian tissues other than brain. Moreover, there is no report on the role of A2b/MAPK-mediated signaling pathway in Aß-induced mitochondrial toxicity in the brain of the experimental animals. Therefore, the present study evaluated the neuroprotective activity of NECA with or without MAPK inhibitor against Aß-induced cognitive deficit and mitochondrial toxicity in the experimental rodents. Further, the effect of NECA with or without MAPK inhibitor was evaluated on Aß-induced mitochondrial toxicity in the memory-sensitive mice brain regions. Intracerebroventricular (ICV) injection of Aß 1-42 was injected to healthy male mice through Hamilton syringe via polyethylene tube to induce AD-like behavioral manifestations. NECA attenuated Aß-induced cognitive impairments in the rodents. In addition, NECA ameliorated Aß-induced Aß accumulation and cholinergic dysfunction in the selected memory-sensitive mouse HIP, PFC, and AMY. Further, NECA significantly attenuated Aß-induced mitochondrial toxicity in terms of decrease in the mitochondrial function, integrity, and bioenergetics in the brain regions of these animals. However, MAPKI diminished the therapeutic effects of NECA on behavioral, biochemical, and molecular observations in AD-like animals. Therefore, it can be speculated that NECA exhibits neuroprotective activity perhaps through MAPK activation in AD-like rodents. Moreover, A2b-mediated MAPK activation could be a promising target in the management of AD.

Ruthenium red, mitochondrial calcium uniporter inhibitor, attenuates cognitive deficits in STZ-ICV challenged experimental animals.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cardinal features of cognitive dysfunction in an individual. Recently, the blockade of mitochondrial calcium uniporter (MCU) exhibits neuroprotective activity in experimental animals. However, the therapeutic potential of MCU has not yet been established in the management of AD. Therefore, the present study explored the therapeutic potential of either Ruthenium red (RR), a MCU blocker, or Spermine, a MCU opener, on the extent of mitochondrial calcium accumulation, function, integrity and bioenergetics in hippocampus, pre-frontal cortex and amygdale of ICV-STZ challenged rats. Experimental AD was induced in male rats by intracerebroventricular injection of streptozotocin (ICV-STZ) on day-1 (D-1) of the experimental protocol at a sub-diabetogenic dose (3 mg/kg) twice at an interval of 48 h into both rat lateral ventricles. RR attenuated ICV-STZ-induced memory-related behavioral abnormalities in Morris water maze and Y-maze tests. RR also attenuated ICV-STZ-induced decrease in the level of acetylcholine and activity of choline acetyltransferase and, increase in the activity of acetylcholinestarase in memory-sensitive rat brain regions. Further, RR attenuated mitochondrial toxicity in terms of reducing mitochondrial calcium accumulation and improving the mitochondrial function, integrity and bioenergetics in memory-sensitive brain regions of ICV-STZ challenged rats. Furthermore, RR attenuated the percentage of apoptotic cells in ICV-STZ challenged rat brain regions. However, Spermine did not alter ICV-STZ-induced behavioral, biochemical and molecular observations in any of the brain regions. These observations indicate the fact that the MCU blockage could be a potential therapeutic option in the management of sporadic type of AD.

Intracerebroventricular streptozotocin administration impairs mitochondrial calcium homeostasis and bioenergetics in memory-sensitive rat brain regions.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cardinal manifestation of cognitive dysfunction. The limitation to avail a successful drug candidate encourages researchers to establish an appropriate animal model in the novel anti-AD drug discovery process. In this context, the mechanism of mitochondrial dysfunction in cognitive deficit animals is yet to be established for intracerebroventricular injection of streptozotocin (ICV-STZ). Experimental dementia was induced in male rats by ICV-STZ on day-1 (D-1) of the experimental protocol at a sub-diabetogenic dose (3 mg/kg) twice at an interval of 48 h into both rat lateral ventricles. ICV-STZ caused cognitive decline in terms of increase in the escape latency on D-14 to D-17 and, decrease in the time spent and percentage of distance travelled in the target quadrant during Morris water maze and decrease in the spontaneous alteration behavior during Y-maze tests in rats. Further, ICV-STZ decreased the level of acetylcholine and activity of choline acetyltransferase and increased the activity of acetylcholinesterase in rat hippocampus, pre-frontal cortex and amygdala. Interestingly, ICV-STZ increased the mitochondrial calcium in addition to decrease in the mitochondrial function, integrity and bioenergetics in all rat brain regions. Further, ICV-STZ enhanced the levels of expression of NR1 subunit of N-methyl-D-aspartate receptor, mitochondrial calcium uniporter and sodium-calcium exchanger in these rat brain regions. Thus, NR1-dependent mitochondrial calcium accumulation could be considered as a major attribute to the animal model of ICV-STZ-induced AD-like manifestations. Further, drugs targeting to manage mitochondrial calcium homeostasis could best be studied in this animal model.

Roflumilast attenuates cognitive deficits in estrogen insufficient rats.

Estrogen replacement therapy including specific estrogen receptor alpha (ERα) agonist, 4,4',4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) trisphenol (PPT), improves cognitive function in the females with estrogen insufficiency condition. It is well suggested that the cyclic nucleotides are considered as one of the downstream mediators to ERα receptor activity and they can be hypothesized as a potential target in the management of estrogen insufficiency condition. Roflumilast, a phosphodiesterase-4 inhibitor, increases the level of cyclic adenosine monophosphate (cAMP) in most of the tissues including the brain, and is reported to have procognitive activity in the experimental animals. Hence, the present study evaluated the therapeutic effect of roflumilast with or without PPT in rats with experimentally-induced estrogen insufficiency. Estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Roflumilast (0.3 and 1.0 mg/kg; p.o.) and PPT (333µg/kg; i.p.) attenuated ovariectomy-induced cognitive deficits in the rodents during behavioral tests. Roflumilast and PPT increased the cholinergic function and cAMP level in the rat hippocampus and prefrontal cortex. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in both the brain regions was attenuated with the monotherapy of either roflumilast or PPT. Interestingly, the combination of 1.0 mg/kg roflumilast and PPT exhibited better therapeutic effectiveness than their monotherapy. In addition, roflumilast facilitated PPT-induced increase in the level of expression of phosphorylated protein kinase-B (Akt) in both the rat brain regions. Hence, it can be assumed that the combination of roflumilast and PPT could be a therapeutic option in the management of estrogen insufficiency-induced disorders.

Vinpocetine facilitates the anti-amnesic activity of estrogen-receptor alpha agonist in bilateral ovariectomy-challenged animals.

The fluctuation in plasma estrogen level influences the cognitive function in the females. The specific estrogen receptor alpha (ERα) agonist, (4,4',4″-(4-propyl-[1 H] pyrazole-1,3,5-triyl) tris phenol (PPT), is reported to exhibit therapeutic activity similar to that of estrogen replacement therapy. However, the former can also exert cyclic adenosine monophosphate (cAMP)-dependent carcinogenic activity in the uterus of the ovariectomized animals. Moreover, there is no report of cGMP on ERα-mediated phosphorylation of Akt in the experimental condition. Vinpocetine increases the rate of formation of cGMP than cAMP in several tissues. Hence, the present study evaluated the neuroprotective effect of vinpocetine with or without PPT against ovariectomy-induced dementia in experimental rodents. The condition of estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Vinpocetine (20 mg/kg) and PPT attenuated ovariectomy-induced cognitive deficits in behavioral tests and increase in body weight in the rodents. Vinpocetine and PPT increased the cholinergic function and the ratio of cGMP/cAMP in the hippocampus, pre-frontal cortex and amygdala of the ovariectomized animals. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in all brain regions was attenuated with the monotherapy of either vinpocetine or PPT. Interestingly, the combination of vinpocetine and PPT exhibited better effectiveness than their monotherapy. However, vinpocetine attenuated the PPT-induced increased level of phosphorylated Akt in discrete brain regions and weight of uterus of these rodents. Hence, the combination could be considered as a better alternative candidate with minimal side effects in the management of estrogen insufficiency-induced disorders.