3R-Refinement principles: elevating rodent well-being and research quality.

This review article delves into the details of the 3R-Refinement principles as a vital framework for ethically sound rodent research laboratory. It highlights the core objective of the refinement protocol, namely, to enhance the well-being of laboratory animals while simultaneously improving the scientific validity of research outcomes. Through an exploration of key components of the refinement principles, the article outlines how these ethics should be implemented at various stages of animal experiments. It emphasizes the significance of enriched housing environments that reduce stress and encourage natural behaviors, non-restraint methods in handling and training, refined dosing and sampling techniques that prioritize animal comfort, the critical role of optimal pain management and the importance of regular animal welfare assessment in maintaining the rodents well-being. Additionally, the advantages of collaboration with animal care and ethics committees are also mentioned. The other half of the article explains the extensive benefits of the 3R-Refinement protocol such as heightened animal welfare, enhanced research quality, reduced variability, and positive feedback from researchers and animal care staff. Furthermore, it addresses avenues for promoting the adoption of the protocol, such as disseminating best practices, conducting training programs, and engaging with regulatory bodies. Overall, this article highlights the significance of 3R-Refinement protocol in aligning scientific advancement with ethical considerations along with shaping a more compassionate and responsible future for animal research.

Efficacy and Safety of Water-Free Lipid Formulation System Containing Calcipotriol Against Psoriasis Vulgaris.

Calcipotriol, a vitamin D analogue is widely used in the treatment of psoriasis. However, poor adherence to topical therapy has led to an ineffective use of the medication and built a barrier to the treatment's success. A water-free lipid-based formulation system has been developed to improve dosage and cosmetic properties along with patient compliance. This study was conducted to evaluate the efficacy and cutaneous safety of water-free lipid-based formulations containing calcipotriol (50 μg/g) as compared to their corresponding vehicles and marketed calcipotriol formulations in a psoriasis plaque test. In total, 24 subjects with chronic psoriasis vulgaris were enrolled in this single-center, randomized, vehicle, and comparator-controlled clinical trial and treated once daily over a 12-day period (10 applications). The anti-psoriatic effect was evaluated by sonographic measurement of psoriatic infiltrate and investigators' clinical efficacy assessments. The mean reduction in psoriatic infiltrate from baseline to day 12 (end of trial) with lipid-based calcipotriol formulations (-34% and -37%) was statistically significant (P<0.0001) when compared to their corresponding vehicles (6% and -4%) but not when compared with marketed calcipotriol solution and cream (-34% and -49% respectively). Mean total clinical assessment scores of these lipid-based calcipotriol formulations (1.7 each) were between those of the two comparators - greater than marketed calcipotriol solution (1.3) but lower than cream (2.0). Overall, nine mild non-serious treatment-emergent adverse effects related to all calcipotriol formulations were reported in four subjects, but all recovered at the follow-up visit. Therefore, novel lipid-based formulations of calcipotriol were clearly more efficacious than their corresponding vehicles and considered as safe therapy against psoriasis vulgaris. J Drugs Dermatol. 2023;22(2):197-202. doi:10.36849/JDD.7151Citation: Holmbäck J, Carlsson A, Rinwa P. Efficacy and safety of water-free lipid formulation system containing calcipotriol against psoriasis vulgaris. J Drugs Dermatol. 2023;22(2):197-202. doi:10.36849/JDD.7151  .

Preclinical development of sodium fusidate antibiotic cutaneous spray based on water-free lipid formulation system.

Topical antibiotics are a key component in the management of mild to moderate skin and soft tissue infections. There are, however, concerns about the emerging bacterial resistance against topical antibacterial agents such as fusidic acid, due to the prolonged treatment period of its marketed dosage forms. Improving the efficacy of topical formulations could potentially shorten the treatment period and avoid the resistance growth. To provide a more effective drug delivery, a water-free lipid-based formulation system (AKVANO®) which can be applied by spraying, has been developed. In the current paper, different formulations containing sodium fusidate were evaluated for their in vitro skin permeability using artificial skin mimicking membranes and antibacterial properties using ex vivo and in vivo skin wound infection models. The novel formulations containing sodium fusidate showed a much higher skin permeation (up to 60% of nominal amount) than the commercially available Fucidin® cream (3%). These formulations also gave a significantly stronger antibacterial effect than Fucidin cream showing a clear dose-response relationship for the sodium fusidate content. A spray product based on the described formulation technology would therefore require a shorter treatment time and thereby lower the risk for the development of bacterial resistance. Spray administration of these formulations provides an even layer on the skin surface from which the solvent quickly evaporates and thereby facilitates a non-touch application where no rubbing is required.

AKVANO®: A Novel Lipid Formulation System for Topical Drug Delivery-In Vitro Studies.

A novel formulation technology called AKVANO® has been developed with the aim to provide a tuneable and versatile drug delivery system for topical administration. The vehicle is based on a water-free lipid formulation where selected lipids, mainly phospholipids rich in phosphatidylcholine, are dissolved in a volatile solvent, such as ethanol. With the aim of describing the basic properties of the system, the following physicochemical methods were used: viscometry, dynamic light scattering, NMR diffusometry, and atomic force microscopy. AKVANO formulations are non-viscous, with virtually no or very minute aggregates formed, and when applied to the skin, e.g., by spraying, a thin film consisting of lipid bilayer structures is formed. Standardized in vitro microbiological and irritation tests show that AKVANO formulations meet criteria for antibacterial, antifungal, and antiviral activities and, at the same time, are being investigated as a non-irritant to the skin and eye. The ethanol content in AKVANO facilitates incorporation of many active pharmaceutical ingredients (>80 successfully tested) and the phospholipids seem to act as a solubilizer in the formulation. In vitro skin permeation experiments using Strat-M® membranes have shown that AKVANO formulations can be designed to alter the penetration of active ingredients by changing the lipid composition.

Demise of nociceptive Schwann cells causes nerve retraction and pain hyperalgesia.

ABSTRACT: Recent findings indicate that nociceptive nerves are not "free", but similar to touch and pressure sensitive nerves, terminate in an end-organ in mice. This sensory structure consists of the nociceptive nerves and specialized nociceptive Schwann cells forming a mesh-like organ in subepidermis with pain transduction initiated at both these cellular constituents. The intimate relation of nociceptive nerves with nociceptive Schwann cells in mice raises the question whether defects in nociceptive Schwann cells can by itself contribute to pain hyperalgesia, nerve retraction, and peripheral neuropathy. We therefore examined the existence of nociceptive Schwann cells in human skin and their possible contribution to neuropathy and pain hyperalgesia in mouse models. Similar to mouse, human skin contains SOX10+/S100B+/AQP1+ Schwann cells in the subepidermal border that have extensive processes, which are intimately associated with nociceptive nerves projecting into epidermis. The ablation of nociceptive Schwann cells in mice resulted in nerve retraction and mechanical, cold, and heat hyperalgesia. Conversely, ablating the nociceptive nerves led to a retraction of epidermal Schwann cell processes, changes in nociceptive Schwann cell soma morphology, heat analgesia, and mechanical hyperalgesia. Our results provide evidence for a nociceptive sensory end-organ in the human skin and using animal models highlight the interdependence of the nerve and the nociceptive Schwann cell. Finally, we show that demise of nociceptive Schwann cells is sufficient to cause neuropathic-like pain in the mouse.

PAD2-Mediated Citrullination Contributes to Efficient Oligodendrocyte Differentiation and Myelination.

Citrullination, the deimination of peptidylarginine residues into peptidylcitrulline, has been implicated in the etiology of several diseases. In multiple sclerosis, citrullination is thought to be a major driver of pathology through hypercitrullination and destabilization of myelin. As such, inhibition of citrullination has been suggested as a therapeutic strategy for MS. Here, in contrast, we show that citrullination by peptidylarginine deiminase 2 (PAD2) contributes to normal oligodendrocyte differentiation, myelination, and motor function. We identify several targets for PAD2, including myelin and chromatin-related proteins, implicating PAD2 in epigenomic regulation. Accordingly, we observe that PAD2 inhibition and its knockdown affect chromatin accessibility and prevent the upregulation of oligodendrocyte differentiation genes. Moreover, mice lacking PAD2 display motor dysfunction and a decreased number of myelinated axons in the corpus callosum. We conclude that citrullination contributes to proper oligodendrocyte lineage progression and myelination.

Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types.

The dorsal horn of the spinal cord is critical to processing distinct modalities of noxious and innocuous sensation, but little is known of the neuronal subtypes involved, hampering efforts to deduce principles governing somatic sensation. Here we used single-cell RNA sequencing to classify sensory neurons in the mouse dorsal horn. We identified 15 inhibitory and 15 excitatory molecular subtypes of neurons, equaling the complexity in cerebral cortex. Validating our classification scheme in vivo and matching cell types to anatomy of the dorsal horn by spatial transcriptomics reveals laminar enrichment for each of the cell types. Neuron types, when combined, define a multilayered organization with like neurons layered together. Employing our scheme, we find that heat and cold stimuli activate discrete sets of both excitatory and inhibitory neuron types. This work provides a systematic and comprehensive molecular classification of spinal cord sensory neurons, enabling functional interrogation of sensory processing.

Quercetin along with piperine prevents cognitive dysfunction, oxidative stress and neuro-inflammation associated with mouse model of chronic unpredictable stress.

Stress occurs in everyday life and persistence of it causes memory loss. Bioflavonoids like quercetin are reported to have poor bioavailability and limited therapeutic potential against stress induced neurological disorders. Therefore, the present study is an attempt to elucidate the therapeutic potency of combination of quercetin with piperine; a bioavailability enhancer against chronic unpredictable stress (CUS)-induced behavioral and biochemical alterations. Laca mice were subjected to a series of stressful events for a period of 28 days. Quercetin (20, 40 and 80 mg/kg, p.o.), piperine (20 mg/kg, p.o.) and their combinations were administered daily 30 min before CUS procedure. Piracetam (100 mg/kg, i.p.) served as a standard control. CUS caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Further, there was significant increase in brain oxidative stress markers and neuro-inflammation (TNF-α). This was coupled with marked rise in acetylcholinesterase and serum corticosterone levels. Co-administration of piperine with quercetin significantly elevated their potential to restore these behavioral, biochemical and molecular changes associated with mouse model of CUS. These results suggest that piperine enhances the neuroprotective effects of quercetin against CUS-induced oxidative stress, neuro-inflammation and memory deficits.

Buspirone along with melatonin attenuates oxidative damage and anxiety-like behavior in a mouse model of immobilization stress.

AIM: Stress is recognized to precipitate anxiety and related psychological problems characterized by a wide range of biochemical and behavioral changes. The present study was carried out to investigate the protective effects of melatonin and buspirone, and their combination, against six hours immobilization stress-induced, anxiety-like behavioral and oxidative damage in mice. METHOD: Male Laca mice were pre-treated with melatonin (2.5, 5 mg·kg(-1)), buspirone (5, 10 mg·kg(-1)), and their combination for consecutive five days. On the 6(th) day, animals were immobilized for six hours, and thereafter various behavioral tests were performed followed by biochemical tests. RESULTS: Immobilization stress significantly impaired body weight, locomotor activity, and caused anxiety-like behavior, along with increased oxidative damage. Pretreatment with melatonin and buspirone significantly improved the loss in body weight and locomotor activity, attenuated anxiety-like behavior (in both the mirror chamber and plus maze performance tasks), further restored the levels of brain total proteins, and caused antioxidant-like effects, as evidenced by reduced lipid peroxidation, nitrite concentration, and restoration of reduced glutathione and catalase activity, as compared to control animals. In addition, combination of melatonin (2.5, 5 mg·kg(-1)) with buspirone (5 mg·kg(-1)) significantly potentiated their protective effects, as compared to their effects individually. CONCLUSION: The present study suggests that melatonin potentiates the beneficial effect of buspirone against immobilization stress-induced, anxiety-like behavioral and oxidative damage in mice possibly by involving a serotonergic mechanism.

Panax quinquefolium involves nitric oxide pathway in olfactory bulbectomy rat model.

Olfactory bulbectomy (OBX) is a well known screening model for depression. Panax quinquefolium (PQ) is known for its therapeutic potential against several psychiatric disorders. Nitric oxide (NO), an intercellular messenger has been suggested to play a crucial role in the pathogenesis of depression. The present study was designed to explore the possible involvement of NO mechanism in the protective effect of PQ against olfactory bulbectomy induced depression. Wistar rats were bulbectomized surgically and kept for a rehabilitation period of two weeks. PQ (50, 100 and 200mg/kg; p.o.) alone and in combination with NO modulators like l-NAME (10mg/kg, i.p.) and l-arginine (100mg/kg; i.p.) were then administered daily for another two weeks. Ablation of olfactory bulbs caused depression-like symptoms as evidenced by increased immobility time in forced swim test, hyperactivity in open field arena, and anhedonic like response in sucrose preference test. Further, OBX caused elevation in serum corticosterone levels and increased oxidative-nitrosative damage. These deficits were integrated with increased levels of neuroinflammatory cytokines (TNF-α), apoptotic factor (caspase-3) and a marked reduction in neurogenesis factor (BDNF) in both cerebral cortex and hippocampal regions of bulbectomized rats. Treatment with PQ significantly and dose-dependently restored these behavioral, biochemical and molecular alterations associated with OBX. Further, pretreatment of l-NAME with subeffective dose of PQ (100mg/kg) significantly potentiated its protective effects; however l-arginine pretreatment reversed the beneficial effects. The present study suggests that protective effect of P. quinquefolium might involve nitric oxide modulatory pathway against olfactory bulbectomy-induced depression in rats.

Possible nitric oxide modulation in the protective effects of rutin against experimental head trauma-induced cognitive deficits: behavioral, biochemical, and molecular correlates.

BACKGROUND: Traumatic head injury is turning out to be a major cause of disability and death. Nitric oxide (NO), an intercellular messenger plays a crucial role in the pathophysiology of several neurologic disorders. Therefore, the present study was designed to investigate the effects of rutin, a well-known flavonoid against cognitive deficits and neuroinflammation associated with traumatic head injury and the probable role of NO pathway in this effect. MATERIALS AND METHODS: Wistar rats were exposed to head trauma using weight drop method and kept for a postsurgical rehabilitation period of 2 wk. Later, animals were administered with rutin (20, 40, and 80 mg/kg; per oral) alone and in combination with NO modulators such as N(G)-nitro-L-arginine methyl ester and L-arginine, daily for another 2 wk. RESULTS: Head injury caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Furthermore, there was a significant rise in acetylcholinesterase activity, oxidative stress, neuroinflammation (tumor necrosis factor α), and neuronal apoptosis (caspase-3) in both cortex and hippocampal regions of traumatized rat brain. Rutin significantly attenuated these behavioral, biochemical, and molecular alterations associated with head trauma. Furthermore, pretreatment of N(G)-nitro-L-arginine methyl ester (10 mg/kg, intraperitoneally), a nonspecific nitric oxide synthase inhibitor, with subeffective dose of rutin (40 mg/kg) potentiated the protective effects; however, pretreatment of L-arginine (100 mg/kg; intraperitoneally), an NO donor, reversed the effects of rutin. CONCLUSIONS: The present study suggests that NO modulation could possibly be involved in the neuroprotective effects of rutin against head trauma-induced cognitive deficits, neuroinflammation, and apoptotic signaling cascade.

Modulation of nitrergic signalling pathway by American ginseng attenuates chronic unpredictable stress-induced cognitive impairment, neuroinflammation, and biochemical alterations.

Prolonged stress causes extensive loss of neurons leading to deficits in cognitive performance. Increasing evidence indicates that accumulation of intercellular messenger, nitric oxide (NO), plays a crucial role in the pathogenesis of memory disorders. American ginseng (AG) is known to show protection in different animal models of neurological diseases; however, its exact mechanism of action is not clearly understood. Therefore, the current study was designed to investigate the interaction of AG against chronic unpredictable stress (CUS)-associated behavioral and biochemical alterations and the probable role of nitrergic pathway in this effect. Male Laca mice were exposed to a series of stressors along with drug/vehicle treatment daily for 28 days. CUS paradigm caused significant impairment in both acquisition and retention memory as measured in Morris water maze and elevated plus maze task. This was coupled with alterations in oxidative stress markers, mitochondrial enzyme complex activities, pro-inflammatory cytokine (TNF-α), and acetylcholinesterase levels in the hippocampus as compared with naïve group. Besides, there was a marked increase in serum corticosterone levels. AG (100, 200 mg/kg; p.o.) treatment significantly improved cognitive impairment; reduced TNF-α, acetylcholinesterase, and corticosterone levels; and attenuated oxidative-nitrergic stress. Furthermore, pre-treatment of L-arginine (100 mg/kg; i.p.), a nitric oxide donor, with subeffective dose of AG (100 mg/kg; p.o.) reversed its protective effects. However, L-NAME (10 mg/kg, i.p.), a non-specific NO synthase inhibitor, potentiated the effects of AG. Our findings suggest that modulation of nitrergic signalling cascade is involved in the protective effects of AG against CUS-induced cognitive dysfunction, oxidative stress, and neuroinflammation.

Microglial inhibitory effect of ginseng ameliorates cognitive deficits and neuroinflammation following traumatic head injury in rats.

Traumatic brain injury produces several neuropathological alterations, some of them are analogous to patients suffering from memory disorders. Role of neuroinflammation and oxidative stress has been suggested in the pathophysiology of brain injury-induced cognitive dysfunction. Therefore, the present study was designed to explore the possible role of ginseng and its interaction with minocycline (microglial inhibitor) against experimental brain trauma-induced behavioral, biochemical and molecular alterations. Wistar rats were exposed to brain traumatic injury using weight-drop method. Following injury and a post-injury rehabilitation period of 2 weeks, animals were administered vehicle/drugs for another 2 weeks. Brain injury caused significant memory impairment in Morris water maze task as evident from increase in escape latency and total distance travelled to reach the hidden platform. This was followed by a significant decrease in time spent in target quadrant and frequency of appearance in target quadrant. Further, there was a significant increase in oxidative stress markers, neuroinflammation (TNF-α and IL-6) and acetylcholinesterase levels in both cortex and hippocampal regions of traumatized rat brain. Ginseng (100 and 200 mg/kg) and minocycline (50 mg/kg) treatment for 2 weeks significantly attenuated all these behavioral, biochemical and molecular alterations. Further, combination of sub-effective doses of ginseng (50 and 100 mg/kg) and minocycline (25 mg/kg) potentiated their protective effects which was significant as compared to their effects alone. The results of the present study suggest that the therapeutic effects of ginseng might involve inhibition of microglial pathway against head trauma-induced cognitive impairment and neuroinflammation in rats.

Stress: Neurobiology, consequences and management.

Stress, both physical and psychological, is attracting increasing attention among neuroresearchers. In the last 20 decades, there has been a surge of interest in the research of stress-induced manifestations and this approach has resulted in the development of more appropriate animal models for stress-associated pathologies and its therapeutic management. These stress models are an easy and convenient method for inducing both psychological and physical stress. To understand the behavioral changes underlying major depression, molecular and cellular studies are required. Dysregulation of the stress system may lead to disturbances in growth and development, and may this may further lead to the development of various other psychiatric disorders. This article reviews the different types of stress and their neurobiology, including the different neurotransmitters affected. There are various complications associated with stress and their management through various pharmacological and non-pharmacological techniques. The use of herbs in the treatment of stress-related problems is practiced in both Indian and Western societies, and it has a vast market in terms of anti-stress medications and treatments. Non-pharmacological techniques such as meditation and yoga are nowadays becoming very popular as a stress-relieving therapy because of their greater effectiveness and no associated side effects. Therefore, this review highlights the changes under stress and stressor and their impact on different animal models in understanding the mechanisms of stress along with their effective and safe management.

Suppression of neuroinflammatory and apoptotic signaling cascade by curcumin alone and in combination with piperine in rat model of olfactory bulbectomy induced depression.

OBJECTIVES: Bilateral destruction of the olfactory bulbs is known to cause behavioral changes analogous to symptoms of depression. Curcumin, a traditional Indian spice is currently being investigated in different psychiatric problems including depression. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study is an attempt to elucidate the neuroprotective mechanism of curcumin and its co-administration with piperine against olfactory bulbectomy induced depression in rats. METHODS: Rats undergone olfactory bulbs ablations were analyzed after post-surgical rehabilitation period of 2 weeks. Animals were then treated with different doses of curcumin (100, 200 and 400 mg/kg; p.o.), piperine (20 mg/kg; p.o.) and their combination daily for another 2 weeks. Imipramine (10 mg/kg; i.p.) served as a standard control. Various behavioral tests like forced swim test (FST), open field behaviour and sucrose preference test (SPT) were performed, followed by estimation of biochemical, mitochondrial, molecular and histopathological parameters in rat brain. RESULTS: Ablation of olfactory bulbs caused depression-like symptoms as evidenced by increased immobility time in FST, hyperactivity in open field arena, and anhedonic like response in SPT along with alterations in mitochondrial enzyme complexes, increased serum corticosterone levels and oxidative damage. These deficits were integrated with increased inflammatory cytokines (TNF-α) and apoptotic factor (caspase-3) levels along with a marked reduction in neurogenesis factor (BDNF) in the brain of olfactory bulbectomized (OBX) rats. Curcumin treatment significantly and dose-dependently restored all these behavioral, biochemical, mitochondrial, molecular and histopathological alterations associated with OBX induced depression. Further, co-administration of piperine with curcumin significantly potentiated their neuroprotective effects as compared to their effects alone. CONCLUSIONS: The present study highlights that curcumin along with piperine exhibits neuroprotection against olfactory bulbectomy induced depression possibly by modulating oxidative-nitrosative stress induced neuroinflammation and apoptosis.

Evaluation of sesamol and buspirone in stress induced anxiety in mice.

OBJECTIVES: The present study was designed to elucidate the effects of sesamol, buspirone and their combination in immobilization stress induced behavioral and biochemical alterations in mice. MATERIALS AND METHODS: Male Laca mice (divided into 10 groups with 6 animals each) were pre-treated with sesamol (5 and 10 mg/kg; p.o.), buspirone (5 and 10 mg/kg; p.o.) and combination of sesamol (5 and 10 mg/kg; p.o.) with buspirone (5 mg/kg; p.o.) for consecutive five days. On the 6(th) day, animals were immobilized for 6 h and various behavioral tests such as body weight, locomotor activity, mirror chamber test and elevated plus maze were carried out. Biochemical estimations such as lipid peroxidation and nitrite concentration, glutathione and catalase levels were done. Data was analyzed using One way ANOVA followed by Tukey's test (P < 0.05) was considered statistical significant. RESULTS: Immobilization stress significantly (P < 0.05) impaired body weight, locomotor activity, induced anxiety like behavioral and oxidative damage as compared to naοve animal. Pretreatment with sesamol (5 and 10 mg/kg; p.o.) and buspirone (5 and 10 mg/ kg; p.o.) significantly (P < 0.05) improved body weight, locomotor activity, and anxiety like behavior in mirror chamber as well as plus maze performance tasks and anti-oxidant like effect as evidenced by reduced lipid peroxidation, nitrite concentration and restoration of reduced glutathione and catalase activity as compared to control animals. Further, co- administration of sesamol (5 and 10 mg/kg) with buspirone (5 mg/kg) significantly (P < .05) potentiated the anti anxiety effects as compared to their effects alone. CONCLUSIONS: The present study suggests that combination of sesamol and buspirone potentiated the antianxiety effects against anxiety induced by immobilization stress and oxidative damage in mice.

Piperine potentiates the protective effects of curcumin against chronic unpredictable stress-induced cognitive impairment and oxidative damage in mice.

Life event stressors are the major vulnerability factors for the development of cognitive disorders. A vital therapeutic for stress related disorders is curcumin, derived from curry spice turmeric. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study was designed to investigate the effect of curcumin and its co-administration with piperine against chronic unpredictable stress (CUS)-induced cognitive impairment and oxidative stress in mice. Male Laca mice were subjected to undergo a battery of stressors for a period of 28 days. Vehicle/drugs were administered daily 30mins before CUS procedure. Chronic stress significantly impaired memory performance (delayed latency time to reach platform in Morris water maze as well as to reach closed arm in elevated plus maze test) and decreased locomotor activity along with sucrose consumption. Further, there was a significant impairment in oxidative parameters (elevated malondialdehyde, nitrite concentration and decreased reduced glutathione, catalase levels) and mitochondrial enzyme complex activities, along with raised acetylcholinesterase and serum corticosterone levels. Chronic treatment with curcumin (200 and 400mg/kg, p.o.) significantly improved these behavioral and biochemical alterations, restored mitochondrial enzyme complex activities and attenuated increased acetylcholinesterase and serum corticosterone levels. In addition, co-administration of piperine (20mg/kg; p.o.) with curcumin (100 and 200mg/kg, p.o.) significantly elevated the protective effect as compared to their effects alone. The results clearly suggest that piperine enhanced the bioavailability of curcumin and potentiated its protective effects against CUS induced cognitive impairment and associated oxidative damage in mice.

Pharmacological investigation of memory restorative effect of riluzole in mice.

OBJECTIVE: Streptozotocin (STZ) and sodium nitrite (NaNO(2)) treatment have been positively correlated with higher incidence of memory loss and experimental dementia. The present study was designed to investigate the potential of the Riluzole, an inhibitor of glutamatergic neurotransmission and activator of TWIK-Related K(+) channels with incidences of memory deficits associated with dementia in mice. MATERIALS AND METHODS: Dementia was induced in Swiss albino mice by intracerebroventricular STZ (ICV) and by subcutaneous NaNO(2) in separate groups of animals. Morris water maze was employed to assess learning and memory of the animals. Biochemical analysis of brain homogenate was performed so as to assess brain acetyl cholinesterase (AChE) activity. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured to assess total oxidative stress. RESULTS: Treatment of ICV STZ and NaNO(2) produced a significant decrease in water maze performance of mice hence reflecting loss of learning and memory. Furthermore, higher levels of brain AChE activity and oxidative stress were observed in these animals. Administration of riluzole (5 and 10 mg/kg intraperitoneally) successfully attenuated memory deficits as well as ICV STZ- and NaNO(2) -induced changes in the levels of brain AChE, TBARS, and GSH. CONCLUSION: The memory restorative effects of riluzole in dementia may involve its multiple functions including anti-oxidative and anticholinesterase properties.

Involvement of PPAR-gamma in curcumin-mediated beneficial effects in experimental dementia.

The present study was undertaken to investigate the possible mechanism of curcumin-mediated beneficial effects in memory deficits associated with experimental dementia. Dementia was induced in Swiss albino mice by administering streptozotocin (3 mg kg(-1)) intracerebroventricularly on first and third day. Morris water maze test was employed to assess learning and memory of the animals. Biochemical analysis of brain homogenate was performed to assess brain acetyl cholinesterase (AChE) activity and total oxidative stress. Streptozotocin (STZ) produced a significant decrease in water maze performance of mice indicative of impairment in spatial reference memory. Curcumin (20 mg/kg p.o. daily for 14 days) successfully attenuated STZ-induced memory deficits. Higher levels of brain AChE activity and oxidative stress were observed in STZ-treated animals, which were significantly attenuated by curcumin. Furthermore, the noted beneficial effect of curcumin on STZ-induced dementia was significantly abolished by pretreatment with PPAR-gamma receptor antagonist bisphenol-A-diglycidyl ether, i.e., BADGE (30 mg/kg intraperitoneally (i.p.)). It may be concluded that the beneficial effects of curcumin are mediated through the activation of PPAR-gamma receptors.