N-Acetylcysteine Ameliorates Neurotoxic Effects of Manganese Intoxication in Rats: A Biochemical and Behavioral Study.

Clinical and experimental evidences reveal that excess exposure to manganese is neurotoxic and leads to cellular damage. However, the mechanism underlying manganese neurotoxicity remains poorly understood but oxidative stress has been implicated to be one of the key pathophysiological features related to it. The present study investigates the effects associated with manganese induced toxicity in rats and further to combat these alterations with a well-known antioxidant N-acetylcysteine which is being used in mitigating the damage by its radical scavenging activity. The study was designed to note the sequential changes along with the motor and memory dysfunction associated with biochemical and histo-pathological alterations following exposure and treatment for 2 weeks. The results so obtained showed decrease in the body weights, behavioral deficits with increased stress markers and also neuronal degeneration in histo-pathological examination after manganese intoxication in rats. To overcome the neurotoxic effects of manganese, N-acetylcysteine was used in the current study due to its pleiotropic potential in several pathological ailments. Taken together, N-acetylcysteine helped in ameliorating manganese induced neurotoxic effects by diminishing the behavioral deficits, normalizing acetylcholinesterase activity, and augmentation of redox status.

Studies on the Neuromodulatory Effects of Ginkgo biloba on Alterations in Lipid Composition and Membrane Integrity of Rat Brain Following Aluminium Neurotoxicity.

Brain contains the highest lipid content involved in various structural and physiological activities such as structural development, neurogenesis, synaptogenesis, signal transduction and myelin sheath formation. Lipids bilayer is essential to maintain the structural integrity for the physiological functions of protein. Impairments in lipid metabolism and its composition can lead to the progression of various brain ailments such as neurodegenerative and neuropsychiatric disorders. Aluminium (Al), the potent neurotoxin has been linked to Alzheimer's disease (AD) like pathology. Al can bind to biomembrane and influence oligomerization and conformational changes of proteins by acting as cross-linkers. The present study evaluated the influence of Ginkgo biloba (GBE) on the lipid profile alterations induced by Al lactate in hippocampal and cortical regions using FTIR spectroscopy. Rats were exposed with 10 mg/kg b.w. (intraperitoneal) of Al lactate for 6 weeks. This was followed by a treatment protocol of GBE (100 mg/kg b.w.) both preexposure (2 weeks) and conjunctive (6 weeks) exposure. A self recovery group was also included, where Al withdrawal was done for 2 weeks post Al exposure. A significant decrease in peak areas of cholesterol, sphingolipids and phospholipids was observed in Al treated groups. Further, polyunsaturated fatty acids and membrane fluidity has also decreased, as revealed by olefinic and methyl asymmetric stretching bands. Al treatment significantly increased the fluorescence polarization, anisotropy and order parameter, which however were normalized following GBE supplementation. Results also showed that pretreatment with GBE provided more beneficial effects on the adverse changes following Al in membrane composition and behavioral outcome.

Modulatory Effects of Ginkgo biloba Against Amyloid Aggregation Through Induction of Heat Shock Proteins in Aluminium Induced Neurotoxicity.

Protein misfolding and aggregation of amyloid beta (Aß) peptide, as well as formation of neurofibrillary tangles (NFTs) are the signature hallmarks of Alzheimer's disease (AD) pathology. To prevent this, molecular chaperones come into play as they facilitate the refolding of the misfolded proteins and cell protection under stress. Here, we have evaluated the possible effects of Ginkgo biloba (GBE) against aggregation of the Aß through activation of heat shock proteins (HSPs) in the Aluminium (Al) induced AD based model. GBE (100 mg/kg body weight) was administered per oral to the female SD rats in conjunction with intraperitoneal (i.p.) injection of Al lactate (10 mg/kg body weight) for six weeks. Pretreated animals were administered GBE for additional two weeks prior to any exposure of Al. GBE administration resulted in decrease in Aß aggregation, ubiquitin deposition, accompanying a significant decline in APP & Tau protein hyperphosphorylation which can be attributed to activation of Heat shock factor (HSF-1) and upregulation in the protein expression of HSPs. Histopathological investigation studies have also shown the decrease in aggregation of Aß peptide by GBE administration. Additionally, the decrease in ROS levels and Aß aggregation by GBE administration prohibited the decline in the neurotransmitter levels and monoamine oxidase levels in hippocampus and cortex. This further caused improvement in learning and memory of the animals. In conclusion, our results indicate that GBE prevents the symptoms of Al induced AD like pathophysiology by upregulating the HSPs levels and decreasing the aggregation load.

Temporal changes in physiological and molecular markers in various brain regions following transient global ischemia in rats.

Several mechanisms are involved in the loss of cellular integrity and tissue destructions in various brain regions during ischemic insult. The affected brain employs various self-repair mechanisms during the poststroke recovery. Therefore, the current study involves time course changes in different brain regions following ischemia in terms of inflammation, oxidative stress and apoptosis for which a bilateral common carotid arteries occlusion model was chosen. The development of oxidative stress was seen with a marked increase in ROS and NO levels with concomitant decrease in GSH levels and also the activities of anti-oxidant enzymes. These alterations were accompanied with decreased levels of neurotransmitters and motor and cognitive deficits at various time points. Increased expressions of various pro-inflammatory cytokines and a decline in BDNF levels in hippocampal regions on 7th day post ischemia, suggesting their role in its pathogenesis. The restoration of BDNF and neurotransmitter levels along with significant decline in inflammatory cytokine levels 14th day onwards following ischemia in hippocampus suggested poststroke recovery. The extent of neuronal damage was found to be increased significantly on 7th day post ischemia as indicated by TUNEL assay and hematoxylin and eosin staining depicting enhanced number of pyknotic neurons in cortical and hippocampal regions. Cortical regions of the ischemic brains were severely affected while hippocampal regions showed significant poststroke recovery, which might attributed to the normalization of BDNF and pro-inflammatory cytokine levels. In conclusion, the present study established the central role of BDNF and pro-inflammatory cytokines in the poststroke recovery. Also, the cortical and hippocampal regions were found to be more susceptible for ischemic injury. As our results indicated, full recovery after ischemic injury in different brain regions was not achieved, therefore further studies with long-term recovery time are required to be conducted.

Curcumin affords neuroprotection and inhibits α-synuclein aggregation in lipopolysaccharide-induced Parkinson's disease model.

Parkinson's disease (PD) pathology is characterized by the abnormal accumulation and aggregation of the pre-synaptic protein α-synuclein in the dopaminergic neurons as Lewy bodies (LBs). Curcumin, which plays a neuroprotective role in various animal models of PD, was found to directly modulate the aggregation of α-synuclein in in vitro as well as in in vivo studies. While curcumin has been shown to exhibit strong anti-oxidant and anti-inflammatory properties, there are a number of other possible mechanisms by which curcumin may alter α-synuclein aggregation which still remains obscure. Therefore, the present study was designed to understand such concealed mechanisms behind neuroprotective effects of curcumin. An animal model of PD was established by injecting lipopolysaccharide (LPS, 5 µg/5 µl PBS) into the substantia nigra (SN) of rats which was followed by curcumin administration (40 mg/kg b.wt (i.p.)) daily for a period of 21 days. Modulatory functions of curcumin were evident from the inhibition of astrocytic activation (GFAP) by immunofluorescence and NADPH oxidase complex activation by RT-PCR. Curcumin supplementation prevented the LPS-induced upregulation in the protein activity of transcription factor NFκB, proinflammatory cytokines (TNF-α, IL-1ß, and IL-1α), inducible nitric oxide synthase (iNOS) as well as the regulating molecules of the intrinsic apoptotic pathway (Bax, Bcl-2, Caspase 3 and Caspase 9) by ELISA. Curcumin also resulted in significant improvement in the glutathione system (GSH, GSSG and redox ratio) and prevented iron deposition in the dopaminergic neurons as depicted from atomic absorption spectroscopy (AAS) and Prussian blue staining, respectively. Curcumin also prevented α-synuclein aggregates in the dopaminergic neurons as observed from gene as well as protein activity of α-synuclein using RT-PCR and IHC. Collectively, our results suggest that curcumin can be further pursued as a candidate drug in the molecules targeted therapy for PD and other related synucleopathies.

Anti-inflammatory effects of Ginkgo biloba extract against trimethyltin-induced hippocampal neuronal injury.

BACKGROUND: Despite the immense neuromodulatory potentials of Ginkgo biloba extract as a memory enhancer, its underlying mechanism seems inadequate particularly with regard to its anti-inflammatory properties. AIM: The objective of the present study is to investigate the protective potentials of Ginkgo biloba extract (GBE) against hippocampal neuronal injury induced by trimethyltin (TMT), a potent neurotoxicant. METHODS: Male SD rats were administered trimethyltin (8.5 mg kg-1 b.wt) single intraperitoneal (i.p.) injection, followed by Ginkgo biloba extract (100 mg kg-1 b.wt i.p) for 21 days. RESULTS: The co-administration of GBE with TMT showed marked improvement in cognitive functions. Concomitantly, there was a significant decrease in oxidative stress as evident by reduction in MDA and total ROS levels. In addition, there was a marked suppression of astrocyte activation (GFAP), transcription factor NFκB and proinflammatory cytokines (TNF-α, IL-1α, 1L-6), which were found to be elevated by TMT administration. Histopathological observations showed remarkable improvement in hippocampal neuronal injury in the conjunctive group. CONCLUSION: Therefore, it is suggested that Ginkgo biloba extract is an effective agent against trimethyltin-induced hippocampal neuronal loss owing to its antioxidative as well as anti-inflammatory properties.

Curcumin protects dopaminergic neurons against inflammation-mediated damage and improves motor dysfunction induced by single intranigral lipopolysaccharide injection.

Various studies have indicated a lower incidence and prevalence of neurological conditions in people consuming curcumin. The ability of curcumin to target multiple cascades, simultaneously, could be held responsible for its neuroprotective effects. The present study was designed to investigate the potential of curcumin in minimizing microglia-mediated damage in lipopolysaccharide (LPS) induced model of PD. Altered microglial functions and increased inflammatory profile of the CNS have severe behavioral consequences. In the current investigation, a single injection of LPS (5 ug/5 µl PBS) was injected into the substantia nigra (SN) of rats, and curcumin [40 mg/kg b.wt (i.p.)] was administered daily for a period of 21 days. LPS triggered an inflammatory response characterized by glial activation [Iba-1 and glial fibrillary acidic protein (GFAP)] and pro-inflammatory cytokine production (TNF-α and IL-1ß) leading to extensive dopaminergic loss and behavioral abnormality in rats. The behavioral observations, biochemical markers, quantification of dopamine and its metabolites (DOPAC and HVA) using HPLC followed by IHC of tyrosine hydroxylase (TH) were evaluated after 21 days of LPS injection. Curcumin supplementation prevented dopaminergic degeneration in LPS-treated animals by normalizing the altered levels of biomarkers. Also, a significant improvement in TH levels as well as behavioral parameters (actophotometer, rotarod, beam walking and grid walking tests) were seen in LPS injected rats. Curcumin shielded the dopaminergic neurons against LPS-induced inflammatory response, which was associated with suppression of glial activation (microglia and astrocytes) and transcription factor NF-κB as depicted from RT-PCR and EMSA assay. Curcumin also suppressed microglial NADPH oxidase activation as observed from NADPH oxidase activity. The results suggested that one of the important mechanisms by which curcumin mediates its protective effects in the LPS-induced PD model is by inhibiting glial activation. Therefore, curcumin could be a potential therapeutic agent for inflammation-driven neurodegenerative disorders like PD, and its neuroprotective role should be explored further.

Downregulation of telomerase activity by diclofenac and curcumin is associated with cell cycle arrest and induction of apoptosis in colon cancer.

Uncontrolled cell proliferation is the hallmark of cancer, and cancer cells have typically acquired damage to genes that directly regulate their cell cycles. The synthesis of DNA onto the end of chromosome during the replicative phase of cell cycle by telomerase may be necessary for unlimited proliferation of cells. Telomerase, a ribonucleoprotein enzyme is considered as a universal therapeutic target of cancer because of its preferential expression in cancer cells and its presence in 90 % of tumors. We studied the regulation of telomerase and telomerase reverse transcriptase catalytic subunit (TERT) by diclofenac and curcumin, alone and also in combination, in 1, 2-dimethylhydrazine dihydrochloride-induced colorectal cancer in rats. The relationship of telomerase activity with tumors suppressor proteins (p51, Rb, p21), cell cycle machinery, and apoptosis was also studied. Telomerase is highly expressed in DMH group and its high activity is associated with increased TERT expression. However, telomerase is absent or is present at lower levels in normal tissue. CDK4, CDK2, cyclin D1, and cyclin E are highly expressed in DMH as assessed by RT-PCR, qRT-PCR, Western blot, and immunofluorescence analysis. Diclofenac and curcumin overcome these carcinogenic effects by downregulating telomerase activity, diminishing the expression of TERT, CDK4, CDK2, cyclin D1, and cyclin E. The anticarcinogenic effects shown after the inhibition of telomerase activity by diclofenac and curcumin may be associated with upregulation of tumor suppressor proteins p51, Rb, and p21, whose activation induces the cells cycle arrest and apoptosis.

Neuroprotective Role of Lazaroids Against Aluminium Chloride Poisoning.

Aluminium (Al) is neurotoxic primarily because of its interference with biological enzymes in key mechanisms of metabolic pathways. Mitochondria being a major site of reactive oxygen species (ROS) production, it seems that the oxidative damage to mitochondrial proteins may underlie the pathogenesis of Al induced neurodegeneration. The present study investigates the effectiveness of the anti-oxidant property of lazaroids (U-74500A), a known lipid peroxidation inhibitor as neuroprotective agent against Al induced neurotoxicity. Al chloride was administered orally at a dose level of 100 mg/kg body wt/day in water and U-74500A was administered at a dose of 0.25 mg/kg body wt i.p. in citrate buffer for a period of 8 weeks on alternate days. Following Al exposure there was a significant increase in lipid peroxidation (LPO), ROS levels and reduction in the activity of mitochondrial complexes in all the three regions of rat brain, i.e., cerebral cortex, mid brain, and cerebellum. This decrease in the activities of electron transport complexes in turn affected the ATP synthesis and ATP levels adversely in the mitochondria. These alterations were also depicted in the histology which shows signs of hypoxia, paucity of neurons in cortical region and loosening of fibers in the white matter. U-74500A co-administration was able to restore alterations in the LPO, ROS levels as well as all the three mitochondrial complexes and caspase expression. Therefore, it is suggested that 21-aminosteroids (lazaroids), by attenuating LPO and mitochondrial dysfunction, holds a promise as an agent that can potentially reduce Al-induced adverse effects in brain.

Downregulation of PI3-K/Akt/PTEN pathway and activation of mitochondrial intrinsic apoptosis by Diclofenac and Curcumin in colon cancer.

Phosphatidylinositol 3-kinase (PI3-K)/PTEN/Akt signaling is over activated in various tumors including colon cancer. Activation of this pathway regulates multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth that underlie the biology of a cancer cell. In the present study, the chemopreventive effects have been observed of Diclofenac, a preferential COX-2 inhibitory non-steroidal anti-inflammatory drugs, and Curcumin, a natural anti-inflammatory agent, in the early stage of colorectal carcinogenesis induced by 1,2-dimethylhydrazine dihydrochloride in rats. The tumor-promoting role of PI3-K/Akt/PTEN signal transduction pathway and its association with anti-apoptotic family of proteins are also observed. Both Diclofenac and Curcumin downregulated the PI3-K and Akt expression while promoting the apoptotic mechanism. Diclofenac and Curcumin administration significantly increased the expression of pro-apoptotic Bcl-2 family members (Bad and Bax) while decreasing the anti-apoptotic Bcl-2 protein. An up-regulation of cysteine protease family apoptosis executioner, such as caspase-3 and -9, is seen. Diclofenac and Curcumin inhibited the Bcl-2 protein by directly interacting at the active site by multiple hydrogen bonding, as also evident by negative glide score of Bcl-2. These drugs stimulated apoptosis by increasing reactive oxygen species (ROS) generation and simultaneously decreasing the mitochondrial membrane potential (ΔΨ M). Diclofenac and Curcumin showed anti-neoplastic effects by downregulating PI3-K/Akt/PTEN pathway, inducing apoptosis, increasing ROS generation, and decreasing ΔΨ M. The anti-neoplastic and apoptotic effects were found enhanced when both Diclofenac and Curcumin were administered together, rather than individually.

Ameliorative Effect of Palm Oil in Aluminum Lactate Induced Biochemical and Histological Implications in Rat Brain.

α-Tocotrienol is one of the major constituents of palm oil. It is a well-known antioxidant and cholesterol-lowering neuroprotectant. To prevent the initiation of Alzheimer's like symptoms, much attention has been shifted to the major role played by antioxidants. Previous epidemiological reports correlate the increasing incidence of developing Alzheimer's disease (AD), to the aluminum (Al) content in drinking water. Al, being a ubiquitous element, has a long history of being particularly reactive towards multiple aspects of neurobiology. So, the current study examines the effect of Al-induced behavioral, biochemical, and histopathological changes in rat brain; and the ameliorative effect of palm oil in reducing the resulting neurotoxicity. The experimental design consisted of 4 groups: control group which received rodent chow diet and water ad libitum; Al group received aluminum lactate (50 mg/kg bw); Al + palm oil group was administered with Al (50 mg/kg bw) and palm oil (60 mg/kg bw); and palm oil group received palm oil (60 mg/kg bw). Al was given by oral gavage once daily for 6 weeks and palm oil was administered intraperitoneally. After 6 weeks of supplementation, Al + palm oil group showed significantly lower malondialdehyde (MDA) content, but higher superoxide dismutase (SOD), catalase (CAT), GST, and GPx activity as compared to Al group. Al group has significantly higher level of MDA content, but lower SOD, CAT, GST, and GPx activity as compared to control group. In conclusion, this study suggested that palm oil was effective in preventing the Al-induced brain damage in rats.

Stress proteins and glial cell functions during chronic aluminium exposures: protective role of curcumin.

Involved in the ongoing debate is the speculation that aluminium is somehow toxic for neurons. Glial cells cope up to protect neurons from this toxic insult by maintaining the glutathione homeostasis. Of late newer and newer roles of glial cells have been depicted. The present work looks into the other regulatory mechanisms that show the glial cells response to pro-oxidant effects of aluminium exposure. In the present investigation we have evaluated the inflammatory responses of the glial cells as well as HSP70-induction during aluminium exposure. Further, the protective role of curcumin is also evaluated. Aluminium was administered by oral gavage at a dose level of 100 mg/kg b.wt/day for a period of 8 weeks. Curcumin was administered i.p. at a dose of 50 mg/kg b.wt./day on alternate days. Enhanced gene and protein expression of HSP70 in the glial fractions of the aluminium exposed animals as compared to the corresponding neuronal population. Aluminium exposure resulted in a significant increase in the NF-κB and TNF-α expression suggesting inflammatory responses. In the conjunctive treatment group of aluminium and curcumin exposure marked reduction in the gene and protein expression of NF-κB and TNF-α was observed. This was further reflected in histopathological studies showing no evidence of inflammation in conjunctive group as compared to aluminium treatment. From the present study, it can be concluded that curcumin has a potential anti-inflammatory action and can be exploited in other toxicological conditions also.

Beneficial effects of folic acid on enhancement of memory and antioxidant status in aged rat brain.

As our population ages, diseases affecting memory and daily functioning will affect an increasing number of individuals, their families and the healthcare system. Therefore, there is a need to study and evaluate effects of certain conditions for anti-aging of the brain. Nutrient supplementation can modify the brain function. The chemistry and function of both the developing and the mature brain are influenced by diet (Fernstrom, Am J Clinical Nutrition 71:1669S-1673S, 2000). Clinical, biochemical, and pathological aspects have shown a correlation between mental symptoms, especially depression and cognitive decline, with high incidence of folate deficiency (Bottiglieri et al., J Neurol Neurosurg Psychiatry 69:562, 2000). In the present study, consequences of folic acid supplementation on brain dysfunction as a result of aging were studied in cerebral cortex, mid brain, and cerebellar regions of rat brain. This study was carried out on 6-, 11-, and 16-month-old rats, which received folic acid at a dose of 5 mg/kg body weight/day for a period of 8 weeks. Respective control groups of the same age groups were also taken. At the end of the treatment duration, behavioral studies were performed and later the animals were killed for various biochemical and histological investigations. Results indicated significant improvement in memory as assessed by active avoidance, passive avoidance, and plus maze tests in the folic acid supplemented aged animals. Significant improvement was also seen in the cellular protective mechanisms where by the activity of superoxide dismutase and catalase enzymes increased in folic acid supplemented group and so was the glutathione content. Increased lipid peroxidation content, a marker of aging, was also found to be decreased during folic acid supplementation in all the three regions of brain in our study. Thus, it can be concluded that folic acid helps in improving the memory status by reducing oxidative stress and maintaining the integrity of neurons during aging.

Neuroprotective effects of carbenoxolone against amyloid-beta 1-42 oligomer-induced neuroinflammation and cognitive decline in rats.

The aggregation of Aß plays a major role in the progression of Alzheimer's disease (AD) and induces neuroinflammation, neurodegeneration and cognitive decline. Recent studies have shown that the soluble aggregates of Aß are the major culprits in the development of these aberrations inside the brain. In this study, we investigated the neuroprotective potential of carbenoxolone (Cbx), which has been found to possess anti-inflammatory and nootropic properties. Male SD rats (250-300 g) were divided into the four groups (n = 8 per group): (1) sham control rats injected with vehicles, (2) Aß 1-42 group rats injected i.c.v. with Aß 42 oligomers (10 µl/rat), (3) Aß 1-42+Cbx group rats injected i.c.v. with Aß 42 oligomers (10 µl/rat) and i.p. with carbenoxolone disodium (20 mg/kg body weight) for six-weeks and (4) Cbx group rats injected i.p. with carbenoxolone disodium (20 mg/kg body weight) for six-weeks. Progressive learning and memory deficits were seen through a battery of behavioral tests and a significant increase in the expressions of GFAP and Iba-1 was observed which resulted in the release of pro-inflammatory cytokines post Aß oligomer injection. The levels of BDNF, Bcl-2 and pCREB were decreased while Bax, caspase-3, caspase-9 and cytochrome c levels were induced. Also, neurotransmitter levels were altered and neuronal damage was observed through histopathological studies. After Cbx supplementation, the expressions of GFAP, IBA-1, pro-inflammatory cytokines, iNOS, nNOS and nitric oxide levels were normalized. The expression levels of pro-apoptotic markers were decreased and neurotrophin levels were restored. Also, neurotransmitter levels and neuronal profile were improved and progressive improvements in behavioural performance were observed. Our results demonstrated that Cbx might have prevented the Aß induced neurodegeneration and cognitive decline by inhibiting the neuroinflammation and inducing BDNF/CREB signalling. These findings suggest that Cbx can be explored as a potential therapeutic agent against the progression of AD.

Neuroprotective effects of hydro-alcoholic extract of Eclipta alba against 1-methyl-4-phenylpyridinium-induced in vitro and in vivo models of Parkinson's disease.

Pathogenesis of Parkinson's disease (PD) specifically involves the degeneration of dopaminergic neurons in the substantia nigra region, which mainly begun with the overwhelmed oxidative stress and neuroinflammation. Considering the antioxidant and other pharmacological properties, Eclipta alba needs to be exploited for its possible neuroprotective efficacy against PD and other neurological disorders. Therefore, the current study was conducted to exemplify the remedial effects of hydro-alcoholic extract of E. alba (EA-MEx) against MPP+-elicited in vitro and in vivo PD models. SH-SY5Y, a neuroblastoma cell culture and male Wistar rats were used to impersonate the hallmarks of PD. Qualitative and quantitative analyses of EA-MEx revealed the presence of quercetin, ellagic acid, catechin, kaempferol, and epicatechin at varying concentrations. EA-MEx was found to deliver considerable protection against MPP+-induced oxidative damages in SH-SY5Y cells. Furthermore, in vivo study also supported the neuroprotective efficacy of EA-MEx, with significant mitigation of behavioral deficits induced by intrastriatal injection of MPP+. Furthermore, the disturbed levels of cellular antioxidant machinery have been significantly improved with the pre-treatment of EA-MEx. Mechanistically, the expression of α-synuclein, tyrosine hydroxylase, and mortalin were also found to be improved with the prior treatment of EA-MEx. Hence, the study suggests Eclipta alba as a suitable candidate for the development of better neuropathological therapeutics.

Maintenance of Amyloid-beta Homeostasis by Carbenoxolone Post Aß-42 Oligomer Injection in Rat Brain.

The equilibrium between cerebral production and clearance of Aß is maintained either by the active removal through blood-brain barrier or by the uptake and degradation through ubiquitin-proteasome system (UPS) and autophagy. The dysfunction of UPS and dysregulation of molecular chaperones such as heat shock proteins (HSPs) is well correlated with the progression of Alzheimer's disease (AD). Therefore, the restoration of heat shock system and UPS appears to be an effective approach to maintain the Aß homeostasis. The alteration in the Aß homeostasis was induced by a single bilateral intrahippocampal injection of Aß 42 oligomers (10 µl/rat) into the dorsal hippocampus of the rat brain. Cbx (carbenoxolone), a HSP inducer and Aß 42 aggregation inhibitor, was tested (20 mg/kg body weight, i.p. for six-weeks) against the altered Aß homeostasis in the rat brain. Aß 42 oligomers downregulated the expression of HSPs and co-treatment with Cbx prevented this decline. Cbx was able to restore the UPS function post Aß 42 oligomer injection. Aß 42 oligomers induced upregulation of the expression levels of APP, BACE-1 and Tau was also normalized after the co-treatment with Cbx. A significant decrease in the thioflavin-T and Aß positive deposits in different regions of the rat brain was observed after Cbx co-treatment. Thus, the present study projects Cbx as a potential candidate for the maintenance of Aß homeostasis through inhibition of amyloid aggregation and restoration of the functioning of molecular chaperones and UPS system in the progression of AD.

Na(+)-stimulated Na+/H+ exchange and an unfavorable Ca2+ homeostasis initiate the cycloxygenase-2 inhibitors-induced apoptotic signals in colonic epithelial cells during the early stage of colon carcinogenesis.

Evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cycloxygenase (COX) and production of the proinflammatory prostaglandin, PGE2, and thus prevent carcinogenesis in the colon. Indeed, one of the specific COX-2 inhibitors, celecoxib, had been accepted by the US FDA for the treatment of familial adenomatous polyposis. However, the molecular mechanism of such inhibition is not clear, although apoptosis appears to be the dominant antiproliferative end effect. The present study delineates the intracellular ionic milieu in the colonocytes that could generate strong apoptotic signals where DMH-induced carcinogenesis was studied in the initiation stage in rats and its regression with the COX inhibitors. While DMH treatment produced a significant elevation in the Na+/H+ exchanger activity and resultant proton efflux, this was reversed by the NSAIDs, particularly so with celecoxib and etoricoxib compared to aspirin. Similarly, the intracellular pH was changed, with more alkalosis noted in DMH, which was reversed by NSAIDs. Also, an intracellular Ca2+ build up was noted by Fura 2 AM, which was also supported by a reduced Ca2+ ATPase and an enhanced inward movement of Ca2+. Further, mitochondrial dysfunction-related cyt C release, increased DNA ladder formation, activation of caspase-3, and cleavage product of poly (ADP-ribose) polymerase (PARP) were not seen in DMH but well noted in NSAIDs. Our results indicate that NSAIDs can induce apoptosis through a change in the colonic Na+/H+ exchange, intracellular pH, and an unfavorable Ca2+ homeostasis.

Effect of concurrent chronic exposure of fluoride and aluminum on rat brain.

The present in vivo study was designed to investigate the toxic potential of fluoride alone and in conjugation with aluminum on the rat brain. The region-specific response of both elements was studied in different regions of brain, namely the cerebrum, cerebellum, and medulla oblongata. Following fluoride exposure, oxidative stress increased significantly, estimated by increased lipid peroxidation and a decrease in the activity of the antioxidant enzyme, superoxide dismutase. The neurotransmitter (e.g., dopamine, norepinephrine, and serotonin) content was also altered. However, these aspects were more pronounced in animals given fluoride and aluminum together. Histological evidence showed deprivation of neuronal integrity with higher magnitude in concurrent fluoride and aluminum exposure, as compared to fluoride alone. Thus, it can be concluded that aluminum appears to enhance the neurotoxic hazards caused by fluoride.

Effect of caffeic acid and rofecoxib and their combination against intrastriatal quinolinic acid induced oxidative damage, mitochondrial and histological alterations in rats.

Oxidative stress has long been implicated in the neurotoxic effects of glutamate acting through N-methyl-D-aspartate (NMDA) receptors. Therefore, present study has been designed to explore the effect of rofecoxib and caffeic acid on the involvement of oxidative stress, mitochondrial dysfunction and neuronal linked with NMDA receptor-mediated excitotoxicity. Caffeic acid, is a well-known antioxidant flavanoid, implicate anti-inflammatory and immunomodulatory like actions. The present study is an attempt to investigate the antioxidant-like effect of caffeic acid and rofecoxib and their combination against QA-induced oxidative damage, mitochondrial dysfunction and histological alterations. Intrastriatal injection of quinolinic acid (300 nmol) significantly increased oxidative stress (raised lipid peroxidation, nitrite concentration, depleted SOD and catalase), altered mitochondrial complex enzyme activities and histological alteration in the ex vivo striatum. Caffeic acid (5 and 10 mg/kg, p.o.) and rofecoxib (10 and 20 mg/kg, p.o.) treatment for 21 days significantly attenuated oxidative damage and impairment in mitochondrial activities of complex enzymes in the ex vivo striatum. Further, combination of sub effective doses of rofecoxib (10 mg/kg, p.o.) and caffeic acid (5 mg/kg, p.o.) potentiated their protective effect which was significant as compared to their effect per se. The present study suggests the therapeutic effect of caffeic acid and rofecoxib combination against QA-induced ex vivo oxidative damage, mitochondrial and histological alterations in rats.