Behavioral and Proteomic Studies Reveal Methylglyoxal Activate Pathways Associated with Alzheimer's Disease.

Diabetes is one of the major risk factors for Alzheimer's disease (AD) development. The role of elevated levels of glucose, methylglyoxal (MGO), and advanced glycation end products (AGEs) in the pathogenesis of AD is not well understood. In this pursuit, we studied the role of methylglyoxal in the pathogenesis of AD in rat models. The elevated plus-maze (EPM) behavioral study indicated that MGO induces anxiety. Treatment of telmisartan (RAGE expression inhibitor) and aminoguanidine (MGO quencher) attenuated MGO induced anxiety. Further, hippocampal proteomics demonstrated that MGO treated rats differentially regulate proteins involved in calcium homeostasis, mitochondrial functioning, and apoptosis, which may affect neurotransmission and neuronal plasticity. The hippocampal tau phosphorylation level was increased in MGO treated rats, which was reduced in the presence of aminoguanidine and telmisartan. The plasma fructosamine level was increased upon MGO treatment. Hippocampal histochemistry showed vascular degeneration and neuronal loss upon MGO treatment. This study provides mechanistic insight into the role of MGO in the diabetes-associated development of AD.

Buspirone, a 5-HT1A agonist attenuates social isolation-induced behavior deficits in rats: a comparative study with fluoxetine.

Social isolation is a potent stressor in both humans and animals that results in increased anger-like emotion, (anger in humans), aggression and suicidal ideation in humans [suicidal trait-related behavior in rats (STRB)]. The study's purpose was to compare the effects of buspirone (BUS) and fluoxetine (Flx) on social isolation-induced behavior deficits in rats. The male Wistar rats were randomized into six groups and caged individually for 14 days except for the non stress control (nSC) group. They were then divided into the following groups, stress control (SC), Flx (30), BUS (10), BUS (20) and BUS (40) and treated from day 14 to day 28. On the last day of treatment behavior parameters were recorded. Serum cortisol, blood pressure (BP) measurement, magnetic resonance imaging (MRI) of the rat's brain and brain-derived neurotrophic factor (BDNF) expression were performed. SC group showed a significant increase in anger-like emotion, aggression, irritability score, learned helplessness, increased cortisol level and reduced BDNF. These behavioral deficits were attenuated by BUS and Flx, Both were found to be equally beneficial in preventing anger-like emotions and aggression. Flx, which has been found to promote suicidal thoughts in people, did not reduce irritability in rats, showing that it did not affect it. BUS significantly improved all behavioral traits also reduced cortisol levels, significantly increased BDNF and normalized BP. Neuroimaging studies in SC brains showed a reduction in amygdala size compared to nSC, BUS treatment mitigated this reduction. Buspirone is effective in preventing social isolation induced behavioural-deficits.

Self-microemulsifying drug delivery system (SMEDDS) of curcumin attenuates depression in olfactory bulbectomized rats.

BACKGROUND: Current therapies for depression remain limited and plagued by various side effects. Problems associated with curcumin administration include poor aqueous solubility and bioavailability issues. Hence to overcome these, curcumin self micro emulsifying drug delivery system (SMEDDS) which will result in a nanosize emulsion droplets when administered in vivo were formulated in the present study. METHODS: Depression was induced by bilateral olfactory bulbectomy and the animals were randomized into 8 groups as normal, control [(vehicle 10 ml/kg, p.o., (per oral)], pure curcumin (10, 20, 40 mg/kg, p.o.), and curcumin SMEDDS (10, 20, 40 mg/kg, p.o). After 14 days of respective treatment, behavioral parameters such as open field test (OFT), ambulation counts and passive avoidance response (PAR) were evaluated. At the end of experiments, blood was withdrawn from r.o.p (retro orbital plexus) for serum cortisol estimation. RESULTS: In OFT, increased central area frequency, peripheral area frequency, central area duration and decreased rearing and grooming were recorded with an increased ambulation counts. In PAR, significant reduction in number of trials and step down from platform was observed in the animals treated with test drug. Serum cortisol level was also found to be decreased in the test groups. CONCLUSION: Behavioral and biochemical estimations in the present study revealed the improved brain permeability and further increase in biological activity of curcumin SMEDDS.

Ferulic acid ameliorates doxorubicin-induced cardiac toxicity in rats.

Ferulic acid (FA) is a phenolic compound with potent antioxidant activity. The objective of the study was to study the protective effects of FA on doxorubicin (Dox)-induced myocardial toxicity in rats. Wistar rats received vehicle (control) or Dox (20 mg/kg, i.p.) or telmisartan (Tel; 10 mg/kg, p.o.) or ferulic acid (20 mg/kg and 40 mg/kg, p.o.) for 7 days followed by treatment with Dox (20) on the fifth day of treatment, except the control group. On day 8, electrocardiographic parameters were recorded followed by blood withdrawal and then the animals were sacrificed for histopathology. Administration of Dox showed prolonged RR, QTc interval, and QRS complex. The levels of serum CK-MB, LDH, IL-1ß, and IL-6 were significantly increased (p < 0.01). Similarly, levels of Ca+2, Mg+2 ATPase, and Ca+2 ATPase and expression of ANP and BNP were significantly higher as compared to the control. In the FA-treated group, ECG was normal. The serum levels of CK-MB, LDH, IL-1ß, and IL-6 were not elevated. Heart tissue Ca+2, Mg+2 ATPase, and Ca+2 ATPase did not show a statistical difference compared to the control group. The FA treatment attenuated the expression of ANP and BNP. FA (20 and 40) augmented myocardial GSH and Na+/K+ ATPase. Histopathology of the heart confirmed the cardioprotective effect of FA.

Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice.

Silymarin, a plant-derived polyphenolic flavonoid of Silybum marianum, elicited significant antidepressant-like activity in an acute restraint stress model of depression. It improved monoamines, mainly 5-hydroxytryptamine (5-HT) levels in the cortex, dopamine (DA) and norepinephrine (NE) in the cerebellum in mice. The present study was undertaken to explore the antidepressant potential of silymarin in chronic unpredictable mild stress (CUMS) induced depressive-like behavior in mice, and to find out its probable mechanism(s) of action, mainly neurogenesis, neuroinflammation, and/or oxidative stress. The mice were subjected to CUMS for 28 days (4 weeks) and administered with silymarin (100 mg/kg and 200 mg/kg), or fluoxetine or vehicle from days 8 to 28 (3 weeks simultaneously). Animals were evaluated for behavioral changes, such as anhedonia by sucrose preference test, behavioral despair by forced swim test, and exploratory behaviors by an open field test. In addition, neurobiochemical alterations, mainly monoamines, 5-HT, NE, DA, neurotrophic factor BDNF, and cytokines, IL-6, TNF-α, oxidant-antioxidant parameters by determining the malondialdehyde formation (an index of lipid peroxidation process), superoxide dismutase (SOD) and catalase (CAT) activity in hippocampus and cerebral cortex along with serum corticosterone were investigated. Our findings reveal that mice subjected to CUMS exhibited lower sucrose preference, increase immobility time without affecting general locomotion of the animals, and reduce BDNF, 5-HT, NE, and DA level, increased serum corticosterone, IL-6 and TNF-α along with an oxidant-antioxidant imbalance in the hippocampus and cerebral cortex. Silymarin significantly reversed the CUMS-induced changes in the hippocampus and cerebral cortex in mice. Thus, the possible mechanism involved in the antidepressant-like activity of silymarin is correlated to the alleviation of monoaminergic, neurogenesis (enhancing 5-HT, NE, and BDNF levels), and attenuation of inflammatory cytokines system and oxidative stress by modulation of corticosterone response, restoration of antioxidant defense system in cerebral cortex and hippocampus.

Silymarin ameliorates experimentally induced depressive like behavior in rats: Involvement of hippocampal BDNF signaling, inflammatory cytokines and oxidative stress response.

Silymarin is a polyphenolic flavonoid of Silybum marianum, exhibited neuroprotection and antidepressant like activity in acute restraint stressed mice. The main objective of the present study is to investigate possible antidepressant like activity of silymarin in experimentally induced depressive behavior in rats. The depressive behaviors were induced in rats by olfactory bulbectomized (OBX) technique. Wistar rats were administered with silymarin at a dose of 100mg/kg and 200mg/kg, by per oral in OBX and sham operated rats. Behavioral (ambulatory and rearing activity and immobility time), neurochemical [serotonin (5-HT), dopamine (DA), norepinephrine (NE) and brain derived neurotrophic factor (BDNF) level], biochemical (MDA formation, IL-6, TNF-α and antioxidants) changes in hippocampus and cerebral cortex along with serum corticosterone were investigated. Rats subjected to OBX elicited significant increase in immobility time, ambulatory and rearing behaviors, reduced BDNF level, 5-HT, DA, NE and antioxidant parameters along with increased serum corticosterone, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex compared to sham operated rats. Administration of with silymarin significantly attenuated immobility time, ambulatory and rearing behaviors, serum corticosterone and improved BDNF expression, 5-HT, DA, NE and antioxidant paradigms in cerebral cortex as well as hippocampus. In addition, silymarin attenuated IL-6, and TNF-α significantly in hippocampus and cerebral cortex in OBX rats. Thus, silymarin exhibits anti-depressant-like activity in OBX rats due to alterations in several neurotransmitters, endocrine and immunologic systems, including BDNF, 5-HT, DA, NE, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex as well as serum corticosterone.

Telmisartan attenuates diabetes induced depression in rats.

BACKGROUND: Role of brain renin angiotensin system (RAS) is well understood and various clinical studies have proposed neuroprotective effects of ARB's. It is also assumed that diabetic depression is associated with activation of brain RAS, HPA axis dysregulation and brain inflammatory events. Therefore, the present study was designed to investigate the antidepressant effect of low dose telmisartan (TMS) in diabetes induced depression (DID) in rats. METHODS: Diabetes was induced by injecting streptozotocin. After 21days of treatment the rats were subjected to forced swim test (FST). The rats, with increased immobility time, were considered depressed and were treated with vehicle or TMS (0.05mg/kg, po) or metformin (200mg/kg, po) or fluoxetine (20mg/kg, po). A separate group was also maintained to study the combination of metformin and TMS. At the end of 21days of treatments, FST, open field test (OFT) and elevated plus maze (EPM) paradigm were performed. Blood was drawn to estimate serum cortisol, nitric oxide (NO), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß). RESULTS: Persistent hyperglycemia resulted in depression and anxiety in rats as observed by increased immobility, reduced latency for immobility, reduced open arm entries and time spent. The depressed rats showed a significant rise in serum cortisol, NO, IL-6 and IL-1ß (p<0.001). TMS antagonized depression and anxiety. It also significantly attenuated serum cortisol, NO, IL-6 and IL-1ß (p<0.001). CONCLUSIONS: Low dose TMS and its combination with metformin normalizes depressive mood, reduces pro-inflammatory mediators and ameliorates the HPA axis function; thereby providing beneficial effects in DID.

Ferulic acid ameliorates chronic constriction injury induced painful neuropathy in rats.

OBJECTIVE: This study focuses on the evaluation of phenolic compound ferulic acid (FA, 4-hydroxy-3-methoxycinnamic acid) in the chronic constriction injury (CCI) of sciatic nerve induced neuropathy in rats. METHODS: Thirty-six animals were randomly divided into six groups. Left sciatic nerve was exposed and ligated, animals in the control, standard, and test groups were treated orally with respective drugs for 21 days. Nociceptive thresholds (THERMAL hyperalgesia, mechanical hyperalgesia, and tactile allodynia) were assessed at 0 days and thereafter every 3 days till 3 weeks. Three weeks later, the sciatic nerve tissue homogenate was prepared and subjected for estimation of oxidative markers namely total protein, nitric oxide, lipid peroxidase, interleukins (IL-1ß and IL-6). RESULTS: Pregabalin (10 mg/kg, p.o.) and ferulic acid (10, 20, 30 mg/kg, p.o.), significantly and dose dependently, decreased all nociceptive thresholds (thermal hyperalgesia, mechanical hyperalgesia, and tactile allodynia) and biochemical markers (total protein, nitric oxide, lipid peroxidase, and interleukins). CONCLUSION: In conclusion, the anti-hyperalgesic effect of FA in rats receiving CCI might partly be attributed to its anti-oxidant and anti-inflammatory activity and is associated with the maintenance of neuropathic pain and could be useful as an adjuvant to conventional medicines.

Antiallergic effect of piperine on ovalbumin-induced allergic rhinitis in mice.

CONTEXT: Allergic rhinitis (AR) is a global health problem that affects a large number of population. Piperine (PIP) has been reported to exhibit anti-inflammatory, anti-histaminic, and immunomodulatory activities; however, its antiallergic profile has not been studied. OBJECTIVE: The objective of the study was to investigate the antiallergic potential of PIP in ova-albumin (OVA)-induced AR, mast cell degranulation (MSD), and OVA-induced paw edema. MATERIALS AND METHODS: Mice were sensitized with OVA alternately on 1, 3, 5, 7, 9, 11, and 13th day. They were treated with either vehicle, PIP (10, 20, and 40 mg/kg, p.o.), or montelukast (10 mg/kg, p.o.) from the 14th to 20th day. On the 21st day, intranasal (OVA: 5% µl) challenge was done. Animals were evaluated for physiological parameters, biochemical parameters, spleen weight, expression of interleukins (IL-6 and IL-1ß), and immunoglobin-E (IgE). Histopathology of nasal mucosa, lungs, and spleen was carried out. MSD and paw edema studies were made to understand the mechanism of action. RESULTS: PIP (10, 20, and 40 mg/kg, p.o.) showed a significant dose-dependent protection with respect to nasal rubbing, redness of nose, and sneezing (p < 0.001) following nasal challenge. PIP dose dependently reduced histamine, NO concentration (p < 0.001), as well as reduced expression of IL-6, IL-1ß, and IgE (p < 0.001) as compared with the control group. Histopathology showed inhibition of infiltration of eosinophils and hyperplasia. It dose dependently reduced MSD and paw edema (p < 0.001). DISCUSSION AND CONCLUSION: PIP acts by mast cell-stabilizing activity, exhibits immunomodulatory and anti-inflammatory activity, thereby providing an effective treatment for AR.

Effect of aqueous extract of Solanum xanthocarpum Schrad. & Wendl. on postmenopausal syndrome in ovariectomized rats.

OBJECTIVE: Solanum xanthocarpum Schrad. & Wendl. (Solanaceae) is present in many Ayurveda compound formulations including Chavanaprasha and Dasamoolarishta. The whole plant is used in conditions such as inflammation, constipation and promoting conception in females. In the present study, we carried out different tests to evaluate the effect of aqueous extract of Solanum xanthocarpum (SXE) in postmenopausal syndrome. METHODS: The study was carried out in bilaterally ovariectomized one-month-old Wistar rats (40-50 g). Bilaterally ovariectomized (OVX) Wistar rats were divided into four groups (n=6) receiving different treatments, consisting of a vehicle (distilled water), aqueous extract of Solanum xanthocarpum at two different doses (200 and 400 mg/kg) administered orally daily for 90 d and standard drug ß estradiol at a dose of 1 mg/kg administered subcutaneously biweekly for 90 d. Estrogenic activity was assessed by vaginal cornification, sexual behavior, serum estradiol and uterine weight to body weight ratio. Antiosteoporotic activity was assessed on the basis of biomechanical and biochemical parameters followed by histopathological studies, and antidepressant activity was assessed by forced swim test. RESULTS: SXE showed presence of steroids. At the dose of 200 mg/kg, it significantly improved all the parameters of sexual behavior (P<0.01), caused vaginal cornification, and increased serum estradiol and uterine weight (P<0.01). It also significantly improved all the parameters of bone strength as well as depression (P<0.01). Histopathology of bones confirmed the above findings. CONCLUSION: The study indicated that SXE may provide an effective treatment in the prevention of postmenopausal symptoms.

Protective effect of hesperetin in rat model of partial sciatic nerve ligation induced painful neuropathic pain: an evidence of anti-inflammatory and anti-oxidative activity.

Behavioral, biochemical and gene expression changes were investigated in a rat model of partial sciatic nerve ligation (PSNL) after administration of hesperetin (20, 50mg/kg; p.o.), pregabalin (10mg/kg; p.o.) or vehicle (1 ml/kg, p.o.). Thirty-six animals were randomly divided into six groups. Left sciatic nerve was exposed and ligated, animals in the control and test groups were treated orally with respective drugs for fifteen days. Nociceptive threshold was assessed on 0 day and thereafter every three days. Three weeks later, sciatic nerve tissue homogenate was prepared and subjected for estimation of oxidative markers namely total protein, nitric oxide, lipid peroxidase, interleukins (IL-1ß and IL-6) and TNF-α. Administration of hesperetin resulted in a dose dependent attenuation in PSNL-induced mechanical and thermal hyperalgesia, mechanical allodynia as well as down regulation of IL-1ß, IL-6 and TNF-α, and biochemical markers. Consequently, it can be concluded that anti-hyperalgesic effect of hesperetin in rats after PSNL may be attributed to various oxidative markers as well as the pro-inflammatory mediators secreted at the injury site. Hesperetin appears to be a promising candidate for the development as a novel therapeutic for the patients suffering from the neuropathic pain.

Diuretic potential of aqueous extract of roots of Solanum xanthocarpum Schrad & Wendl, a preliminary study.

In traditional system of medicine S. xanthocarpum is used treating difficulty in urination and renal calculus. The objective of the present study was to scientifically evaluate diuretic potential of S. xanthocarpum. The study was divided into two phases of evaluation (acute and sub-acute) with administration of aqueous extract of S. xanthocarpum roots. The animals were treated with either aqueous extract of S. xanthocarpum (AqSX; 200, 400 mg/kg, po) or furosemide (25 mg/kg, po) or hydrochlorthiazide (HCTZ; 25 mg/kg, po). In acute study, the treated animals were observed for urine volume, urine pH, urine and serum electrolytes and creatinine after 6th and 24th h. While in sub-acute study observations for above mentioned parameters were done on day 1, day 7 and day 14. Diuretic index, natriuretic and saluretic potential were also calculated. The results indicated strong diuretic potential with AqSX (400 mg/kg). The diuretic prospective of AqSX was similar to furosemide without any type of toxicity based on the observations of serum electrolytes, serum creatinine and urine creatinine measurement. The findings support ethnobotanical use of S. xanthocarpum.