Article

Protective Effects of Geraniol (a Monoterpene) in a Diabetic Neuropathy Rat Model: Attenuation of Behavioral Impairments and Biochemical Perturbations

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Abstract

Involvement of oxidative stress, inflammatory response, and mitochondrial dysfunction in the development of diabetic neuropathy (DN) is well appreciated. The present study examines the potential of geraniol (GE), a well-known phytoconstituent commonly found in lemon, spices, rose oil, etc., to attenuate DN-associated oxidative/nitrosative stress by employing a streptozotocin (STZ) diabetic rat model. STZ-induced diabetic rats provided with oral supplements of GE (100 mg/kg bw/day, 8 weeks) exhibited significant improvement in tail-flick latency (sensory function) and the narrow beam test (motor function). Terminally, elevated levels of oxidative markers (reactive oxygen species, malondialdehyde, hydroperoxides) in cytosol of the sciatic nerve (SN) and in selected regions of the brain of diabetic rats were markedly reduced by GE supplements. Furthermore, GE significantly diminished the levels of protein carbonyls (a measure of protein oxidation) and nitrites in diabetic rats. In addition, in mitochondria, GE supplements restored the activities of enzymes, such as complexes I–III, succinate dehydrogenase, and citrate synthase, in brain regions of diabetic rats, with a concomitant reduction in the levels of oxidative markers. GE significantly lowered the enhanced cytosolic calcium levels and acetylcholinesterase activity in the SN and the brain regions of diabetic rats. Depleted dopamine levels evident in the SN and the cortex/striatum among diabetic rats were restored by GE. From our data, we hypothesize that GE may be a promising therapeutic candidate in the management of DN in humans. Further understanding of the molecular mechanisms of its neuromodulatory effects is essential in order to exploit its therapeutic efficacy. © 2014 Wiley Periodicals, Inc.

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... In the present model, GE supplemented ACR rats exhibited significant elevation in the levels of GSH and total thiols along with the activities of GSH related enzymes in both SN and brain regions. [51]. These findings corroborate our earlier observations in the diabetic rat model [51] and ACR model of neurotoxicity in Drosophila [26]. ...
... [51]. These findings corroborate our earlier observations in the diabetic rat model [51] and ACR model of neurotoxicity in Drosophila [26]. Interestingly, the protective effect of GE against ACR-induced neurotoxicity was comparable with that of CU. ...
... Although we have not measured the activity of monoamine oxidase, it is speculated that the DA levels were enhanced due to the ability of CU to inhibit ACR induced elevated monoamine oxidase activity [64]. Interestingly, with GE supplementation we have observed a similar restorative effect in SN and brain region (Ct/St) among diabetic rats [51]. This corroborates the previous reports on the involvement of the dopaminergic system in anti-hypersensitivity response (hyperalgesia/allodynia) under neuropathic condition [66]. ...
... According to IDF Diabetes Atlas 9 th edition estimates, about 463 million people are afflicted with diabetes, and this number will double by 2025 [1]. It is one of the common chronic complications in which pain is characterized by mechanical and thermal hyperalgesia [2,3]. Increased glucose levels mediated glycation product formation, autoxidative glycosylation, and elevated polyol pathway activity, which are some of these underlying mechanisms. ...
... The time taken for flicking response (tail withdrawal) was recorded. A cutoff time of 15 s was maintained in all cases [3]. ...
... The time taken for tail withdrawal (flicking response) was recorded. A cutoff time of 25 s was maintained in all cases [3]. ...
Article
Background Diabetic neuropathy (DN) is a condition resulting due to high glucose level. DN is closely linked to oxidative stress and mitochondrial dysfunctions by many pathophysiological pathways that lead to loss of sensation. Aim The current study targeted to elucidate the effect of astaxanthin (AX), a potent antioxidant, on blood glucose level, behavioral impairments specifically evaluating its effects on diabetic neuropathy. We further studied its effect on oxidative stress and mitochondrial dysfunction in diabetic neuropathic mice. Methods The study was conducted by inducing diabetes in Swiss albino mice using STZ (40 mg/kg i.p.). Neuropathy was confirmed in diabetic mice by hot hyperalgesia and cold allodynia tests. To study the protective effects of AX, we administered AX intraperitonially for 4 weeks in consecutive increasing dosage of 2 and 4 mg/kg. Blood glucose levels and body weight were monitored after AX administration. Thereafter, mice were sacrificed and used to estimate levels of different oxidative stress markers along with mitochondrial function in different sections of the brain. Results Astaxanthin (2 and 4 mg/kg, i.p.) administration attenuated STZ-induced alternation in behavioral impairments in DN mice. AX also significantly reduced the levels of blood glucose(p < 0.01), reactive oxygen species (ROS), malondial-dehyde (MDA), nitric oxide (NO), and boosted the antioxidant defenses viz. superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSH), glutathione peroxidase (GPx), thioredoxin reductase (TRR), and acetylcholinesterase (AChE) significantly (p < 0.001) after 4 weeks. In mitochondria, AX increased the activity of enzymes like (complexes I-III), citrate synthase (CS), succinate dehydrogenase (SDH) significantly (p < 0.001) in the different brain sections of DN mice. Conclusion This study reveals that AX normalized blood glucose, oxidative stress, mitochondrial dysfunction and leads to amelioration of behavioral impairments in DN mice.
... According to IDF Diabetes Atlas 9 th edition estimates, about 463 million people are afflicted with diabetes, and this number will double by 2025 [1]. It is one of the common chronic complications in which pain is characterized by mechanical and thermal hyperalgesia [2,3]. Increased glucose levels mediated glycation product formation, autoxidative glycosylation, and elevated polyol pathway activity, which are some of these underlying mechanisms. ...
... The time taken for flicking response (tail withdrawal) was recorded. A cutoff time of 15 s was maintained in all cases [3]. ...
... The time taken for tail withdrawal (flicking response) was recorded. A cutoff time of 25 s was maintained in all cases [3]. ...
... According to IDF Diabetes Atlas 9 th edition estimates, about 463 million people are afflicted with diabetes, and this number will double by 2025 [1]. It is one of the common chronic complications in which pain is characterized by mechanical and thermal hyperalgesia [2,3]. Increased glucose levels mediated glycation product formation, autoxidative glycosylation, and elevated polyol pathway activity, which are some of these underlying mechanisms. ...
... The time taken for flicking response (tail withdrawal) was recorded. A cutoff time of 15 s was maintained in all cases [3]. ...
... The time taken for tail withdrawal (flicking response) was recorded. A cutoff time of 25 s was maintained in all cases [3]. ...
Article
Background Diabetic neuropathy (DN) is a condition resulting due to high glucose level. DN is closely linked to oxidative stress and mitochondrial dysfunctions by many pathophysiological pathways that lead to loss of sensation. Aim The current study targeted to elucidate the effect of astaxanthin (AX), a potent antioxidant, on blood glucose level, behavioral impairments specifically evaluating its effects on diabetic neuropathy. We further studied its effect on oxidative stress and mitochondrial dysfunction in diabetic neuropathic mice. Methods The study was conducted by inducing diabetes in Swiss albino mice using STZ (40 mg/kg i.p.). Neuropathy was confirmed in diabetic mice by hot hyperalgesia and cold allodynia tests. To study the protective effects of AX, we administered AX intraperitonially for 4 weeks in consecutive increasing dosage of 2 and 4 mg/kg. Blood glucose levels and body weight were monitored after AX administration. Thereafter, mice were sacrificed and used to estimate levels of different oxidative stress markers along with mitochondrial function in different sections of the brain. Results Astaxanthin (2 and 4 mg/kg, i.p.) administration attenuated STZ-induced alternation in behavioral impairments in DN mice. AX also significantly reduced the levels of blood glucose(p < 0.01), reactive oxygen species (ROS), malondial-dehyde (MDA), nitric oxide (NO), and boosted the antioxidant defenses viz. superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSH), glutathione peroxidase (GPx), thioredoxin reductase (TRR), and acetylcholinesterase (AChE) significantly (p < 0.001) after 4 weeks. In mitochondria, AX increased the activity of enzymes like (complexes I-III), citrate synthase (CS), succinate dehydrogenase (SDH) significantly (p < 0.001) in the different brain sections of DN mice. Conclusion This study reveals that AX normalized blood glucose, oxidative stress, mitochondrial dysfunction and leads to amelioration of behavioral impairments in DN mice.
... According to IDF Diabetes Atlas 9 th edition estimates, about 463 million people are afflicted with diabetes, and this number will double by 2025 [1]. It is one of the common chronic complications in which pain is characterized by mechanical and thermal hyperalgesia [2,3]. Increased glucose levels mediated glycation product formation, autoxidative glycosylation, and elevated polyol pathway activity, which are some of these underlying mechanisms. ...
... The time taken for flicking response (tail withdrawal) was recorded. A cutoff time of 15 s was maintained in all cases [3]. ...
... The time taken for tail withdrawal (flicking response) was recorded. A cutoff time of 25 s was maintained in all cases [3]. ...
Article
Background Diabetic neuropathy (DN) is a condition resulting due to high glucose level. DN is closely linked to oxidative stress and mitochondrial dysfunctions by many pathophysiological pathways that lead to loss of sensation.AimThe current study targeted to elucidate the effect of astaxanthin (AX), a potent antioxidant, on blood glucose level, behavioral impairments specifically evaluating its effects on diabetic neuropathy. We further studied its effect on oxidative stress and mitochondrial dysfunction in diabetic neuropathic mice.Methods The study was conducted by inducing diabetes in Swiss albino mice using STZ (40 mg/kg i.p.). Neuropathy was confirmed in diabetic mice by hot hyperalgesia and cold allodynia tests. To study the protective effects of AX, we administered AX intraperitonially for 4 weeks in consecutive increasing dosage of 2 and 4 mg/kg. Blood glucose levels and body weight were monitored after AX administration. Thereafter, mice were sacrificed and used to estimate levels of different oxidative stress markers along with mitochondrial function in different sections of the brain.ResultsAstaxanthin (2 and 4 mg/kg, i.p.) administration attenuated STZ-induced alternation in behavioral impairments in DN mice. AX also significantly reduced the levels of blood glucose(p < 0.01), reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), and boosted the antioxidant defenses viz. superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSH), glutathione peroxidase (GPx), thioredoxin reductase (TRR), and acetylcholinesterase (AChE) significantly (p < 0.001) after 4 weeks. In mitochondria, AX increased the activity of enzymes like (complexes I–III), citrate synthase (CS), succinate dehydrogenase (SDH) significantly (p < 0.001) in the different brain sections of DN mice.Conclusion This study reveals that AX normalized blood glucose, oxidative stress, mitochondrial dysfunction and leads to amelioration of behavioral impairments in DN mice.
... Group I (Control group): The rats received a subcutaneous injection of 0.9% saline (vehicle) at a dose of 0.2 ml/day and equal volume of edible oil orally for 8 weeks. Group II (geraniol group): The rats received a subcutaneous injection of 0.9% saline (vehicle) at a dose of 0.2 ml/day and geraniol (100 mg/kg/day) dissolved in edible oil orally for 8 weeks [12]. Group III (d-galactose group): The rats were subcutaneously injected with d-gal (100 mg/kg/day) for 8 consecutive weeks [13]. ...
... Group III (d-galactose group): The rats were subcutaneously injected with d-gal (100 mg/kg/day) for 8 consecutive weeks [13]. Group IV (d-galactose + geraniol group): The rats received a subcutaneous injection of d-gal in the same dose as group III along with geraniol (100 mg/kg/day) dissolved in edible oil orally for 8 weeks [12]. The decided dose of GE was selected upon a preliminary pilot study. ...
... In contrast, our results showed that GE markedly reversed changes in the AchE activity and Ach level. These results are in accordance with the results of Prasad [12]. Accumulating evidence revealed that the brain has the highest oxygen demand in the body and weak antioxidant mechanism. ...
Article
Full-text available
Geraniol (GE), an important ingredient in several essential oils, displayed pleiotropic biological activities through targeting multiple signaling cascades. In the current study, we aimed to examine the protective effect of GE on d-galactose (d-gal) induced cognitive impairment and explore the underlying mechanisms. Forty male Wistar rats (8 weeks old) were randomly categorized into 4 groups; Group I (saline + vehicle [edible oil]), group II (saline + geraniol) (100 mg/kg/day orally), group III (d-galactose) (100 mg/kg/day subcutaneously injected), and group IV (d-galactose + geraniol). Behavioral impairments were evaluated. Brain levels of malondialdehyde (MDA) and reduced glutathione (GSH) as well as superoxide dismutase (SOD) and acetylcholinesterase (AchE) activities were estimated. The levels of inflammatory markers [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and nuclear factor kappa beta (NF-kβ)], endoplasmic reticulum stress sensors [inositol requiring protein 1(IRE1) and protein kinase RNA–like endoplasmic reticulum kinase (PERK)], brain-derived neurotrophic factor (BDNF), and mitogen-activated protein kinases (MAPK) pathway were measured by ELISA. Also, hippocampal histopathological assessment and immunohistochemical analysis of glial fibrillary acidic protein (GFAP) and caspase-3 were performed. Glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) mRNA expression and protein levels were assessed. GE effectively ameliorated aging-related memory impairment through increasing GSH, BDNF, Ach levels, and SOD activity. Additionally, GE treatment caused a decrease in the levels of MDA, inflammatory mediators, and ER stress sensors as well as the AchE activity together with concomitant down-regulation of GRP78 and CHOP mRNA expression. Moreover, GE improved neuronal architecture and rat's spatial memory; this is evidenced by the shortened escape latency and increased platform crossing number. Therefore, GE offers a unique pharmacological approach for aging-associated neurodegenerative disorders. Graphical Abstract
... It is also found in a wide range of cleansing products and cosmetics for its appealing odor [13,14]. In the recent past, several studies have recognized the pharmacological potential of GE in different models [15][16][17]. Its pharmacological property is by virtue of its antioxidant and anti-inflammatory properties [18,19]. ...
... This was followed by the investigation of the modulatory potency of GE in SHSY5Y, neuroblastoma cell line, under hyperglycemic condition simulating DN. These studies were designed based on the data pertaining to the modulatory effects of GE obtained in in vivo studies from the same lab earlier [16,21]. ...
... GE has been reported as an effective antioxidant and antiinflammatory agent in different experimental models from our lab and others [16][17][18][19]21,29]. Recently, the antioxidant activity of GE along with other actives has been published with respect to DPPH free radical scavenging activity and superoxide dismutase activity [30]. ...
Article
Full-text available
Objective: The aim of this study was to analyze antioxidant effect of geraniol (GE) in different in vitro models.Methods: Initially, the antioxidant activity of GE was assessed by diphenyl picrylhydrazyl radical (DPPH) assay. The modulatory effect of GE against 2,2’-azobis(2-amidinopropane) dihydrochloride induced lipid peroxidation in rat brain regions (cortex and cerebellum) and sciatic nerve (SN) homogenates was determined. Further, the effect of GE was assessed against hyperglycemia-induced oxidative stress (OS) in SHSY5Y, a human neuroblastoma cell line.Results: GE proved to be a good scavenger of DPPH free radical (inhibitory concentration 50% [IC50] value = 663 nmol) and could lower the lipid peroxidation levels in rat brain tissue and SN homogenates (25-40%). Further, it rescue the SHSY5Y cells from hyperglycemia-induced death. Co-exposure of GE with the IC50 level of glucose (100 mM) lowered the levels of reactive oxygen species, hydrogen peroxides and 3-nitrotyrosine levels with concomitant elevation in the glutathione levels (about two folds).Conclusion: Collectively from these findings and other studies previously conducted (from our lab and others) emphasize the potential benefit of GE against OS, a progressive pathological feature of neurodegenerative disorders.
... 15 Recently, increasing evidence has suggested that the levels of oxidative markers (reactive oxygen species, malondialdehyde [MDA], and hydroperoxides) increase in the sciatic nerve of diabetic rats. 16,17 Evidence supports the involvement of inflammatory response, oxidative stress, and energy depletion in the progress of diabetic neuropathy. 18,19 No studies have investigated a therapeutic approach that combines insulin and treadmill training for managing diabetic neuropathy. ...
... The present data are in agreement with a previous experiment showing that the administration of resveratrol produced a marked reduction of nerve MDA contents in diabetic rats, which may contribute to the decrease in IL-6 and TNF-α in the sciatic nerves of acute STZ-induced diabetic rats as well. 15 In addition, Prasad and Muralidhara 16 reported that geraniol regulates neurotransmission, mitochondrial function, and oxidative stress markers under diabetic neuropathy conditions. Furthermore, another study has shown that zinc application attenuates the functional decline of peripheral nerves in diabetic rats and provides a protective effect, which may be involved in its inhibitory action on oxidative stress through decreasing MDA expression and through modulating metallothionein contents. ...
Article
Insulin therapy plays a critical role in managing type 1 diabetes mellitus, and exercise produces alterations in pain sensation. This experiment explored the effects of insulin therapy combined with treadmill training on diabetic neuropathic pain and on the expression of malondialdehyde (MDA) and cytokines. Rats were given 4 weeks of insulin (100 IU/kg) therapy and treadmill training (30-60 min/d of training at 20-25 m/min) each day beginning on day 3 after streptozotocin (65 mg/kg, IV) injection and continuing until day 27. Sensitivity to heat and mechanical stimuli and the expression of interleukin (IL)-10, IL-6, tumor necrosis factor-α, and MDA in the sciatic nerve were estimated. We showed that 2 to 4 weeks of treadmill training, insulin treatment, or their combination increased both paw withdrawal thresholds and latencies compared with the same regimen in sedentary diabetic rats (all P < 0.0022). Treatment with insulin, but without treadmill training, had significant effects on glycemic control (P < 0.0001) and restored body weight (P < 0.0001) in the diabetic rats. The diabetic rats demonstrated the upregulation (all P < 0.009) of IL-6, MDA, and tumor necrosis factor-α in the sciatic nerve on days 14 and 28 after streptozotocin treatment, whereas in diabetic rats receiving insulin, treadmill training, or a combination (all P < 0.01), this upregulation was decreased. Insulin, treadmill training, or the combination increased IL-10 expression (all P < 0.0051) in all diabetic rats. Treadmill training combined with insulin therapy showed the best improvements in tactile allodynia and thermal hyperalgesia among our 3 treatment groups. The benefits of insulin intervention and treadmill training could be related to chronic inflammation (proinflammatory cytokines) and oxidative stress (MDA).
... Geraniol has been reported to have multiple activities that include anti-inflammatory, hepatoprotective, anti diabetic and neuroprotective action. [26] It has been demonstrated to reduce blood glucose and glycated haemoglobin [27] and neuropathy [28] ; however, the mechanism of such action is not reported earlier. The inhibition of intestinal transport by almost 60.28% has the potential to lower postprandial spikes, as GLUT2 accounts for almost 75% of the glucose transport. ...
Article
Objective: To isolate and identify the bioactive component from Cymbopogon martinii having GLUT2 transporter inhibitory activity - towards development of a novel strategy for treatment of diabetes mellitus. Method: Isolation of bioactive component was carried out using differential solvent extraction, HPTLC and HPLC, and identification was done by GC-MS. In-vitro studies on intestine, liver, kidney and in-vivo assessment by OGTT and long-term treatment on diabetic rats were carried out. Key findings: Geraniol was isolated and identified as bioactive component. Intestinal glucose absorption demonstrated 60.28% inhibition of transport at 648.34 μm of geraniol. It was found to inhibit glucose release from liver on adrenaline challenge by 89.82% at 324.17 μm/ml. Kidney glycogen content doubled using 648.34 μm of geraniol as compared to control. Geraniol demonstrated 2.14 times higher renal glucose output than diabetic control. OGTT demonstrated prevention of postprandial spikes. Prolonged treatment for 60 days with 29.37 mm/kg B.W. twice a day of geraniol improved the lipid profile, HbA1C levels and renal parameters. In mRNA studies for 10 days, over expression of GLUT2 was prevented by geraniol. Conclusions: Inhibition of GLUT2 by geraniol has the potential to reduce hyperglycaemia and prevent secondary complications in diabetes.
... Other mechanisms such as a reduction in intracellular calcium levels by GOH could also result in lower ERK activation. GOH has been shown to decrease cytosolic calcium levels in nervous tissues of diabetic rats [30] and to inhibit L-type calcium channels in mouse cardiomyocytes and guinea pigs heart tissue [18]. Cardiac function and viability are tightly regulated by calcium cellular levels. ...
Article
Aims: Reactive oxygen species (ROS) are generated in the ischaemic myocardium especially during early reperfusion and affect myocardial function and viability. Monoterpenes have been proposed to play beneficial roles in diverse physiological systems; however, the mechanisms of action remain largely unknown. This study aims to assess the effect of monoterpene geraniol (GOH) on neonatal rat ventricular cardiomyocytes (NRVCs) subjected to oxidative stress. Main methods: We used an in vitro model of hypoxia-reoxygenation. Cardioprotective (AMPK) and cardiotoxic (ERK1/2, ROS) signaling indicators were measured. Assays were performed by fluorogenic probes, MTT assays and Western-blots. Key findings: We determined that the addition of GOH (5-200μM) to cultured normoxic and hypoxic-NRVCs diminished the endogenous production of ROS in stressed cardiomyocytes. We observed that GOH treatment increased pAMPK levels and decreased pERK1/2 levels in cultured NRVCs. Significance: This report suggests that GOH is a candidate cardioprotective natural compound that operates by blunting the oxidative stress signaling that is normally induced by hypoxia-reoxygenation.
... GE could alleviate cytosolic calcium levels and acetylcholinesterase activity. Meanwhile, GE could inhibit the protein of carbonyls and nitrites [61]. GE attenuates another diabetic induced complication, i.e., diabetes-induced cardiac functional disorder, by inhibiting oxidative stress and decreasing hyperglycemia. ...
Article
Geraniol is an acyclic isoprenoid monoterpene isolated from the essential oils of aromatic plants including Cinnamomum tenuipilum, Valeriana officinalis, and several other plants. The limited source of geraniol from plant isolation cannot fulfill the great demand from the flavor and fragrance industries, which require maximizing geraniol production through biotechnology processes. The diverse activities of geraniol suggested that geraniol could treat various diseases as a promising drug candidate. In order to evaluate the potential of geraniol applied in a clinical trial, this review aims at providing a comprehensive summary of the pharmacological effects of geraniol. The publications retrieved from PubMed, ScienceDirect, Springer, and Wiley databases were collected and summarized for the last 6 years. Then, the potential application of geraniol as a drug is discussed based on its pharmacological properties, including antitumor, anti-inflammatory, antioxidative, and antimicrobial activities, and hepatoprotective, cardioprotective, and neuroprotective effects. Hence, this review aims at providing evidence of the pharmacological activities of geraniol in the context of further development as a drug candidate in clinical application.
... 17 Moreover, α-terpineol exerted cytostatic activities against many human cancer cell lines such as leukemia, ovarian, breast adenocarcinoma and chronic myeloid leukemia. 18 Bicas et al 19 showed that α-terpineol had an antioxidant potential similar to BHA (butylated hydroxyanisole) and possess a potential protective activity in foodstuffs. The antioxidant activity of geraniol has been reported by several authors. ...
Article
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Introduction: Solenostemma oleifolium is a species that grows in extremely dry conditions. It is widespread at the foot of cliffs and in rocky areas. It is a medicinal plant used for the treatment of diabetes, respiratory disorders, rheumatism, stomach pain, urinary tract infections and febrifuge. As a part of this research program on natural compounds with antioxidant properties, the main objective of this study was to determine the chemical composition and the antioxidant activity of essential oil of S. oleifolium. Material and Methods: In this study, the aerial parts of the plant were hydrodistilled in a Clevenger-type apparatus. The isolated essential oil was analyzed using gas chromatography mass spectrometry (GC-MS). The antioxidant activity of the essential oil was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric-reducing power (FRAP). Results: The essential oil of S. oleifolium was principally characterized by oxygenated monoterpenes (94.3%) represented by linalool (59.0%), α-terpineol (14.5%) and geraniol (12.4%), followed by small amounts of nerol (3.7%) and piperitone (3.6%). The results of the antioxidant activity of essential oil showed an interesting propriety in the quenching of DPPH radical, with an IC50 of 3.3 g/L. On the other hand, essential oil showed the presence of the reductive effect, which increased with an increase in concentration. Conclusions: The results of this research showed that the S. oleifolium essential oil presented an interesting antioxidant property. Actually, it could be proposed as a new potential source of natural additives for the food or pharmaceutical industries. Keywords: Essential Oil, Antioxidant Activity, Solenostemma Oleifolium, DPPH, FRAP
... However, geraniol was effective in restoring oxidative balance and diminishing renal TGF-β contents. Various previous studies proved the antioxidant potential of geraniol which could be utilized in management of several disorders (Ahmad et al. 2011;Prasad 2014;Prasad and Muralidhara 2017). Control rat demonstrating no histochemical reactions, STZ-injected rat demonstrating observable thickening of glomerular basement membrane, geraniol and gliclazide-treated diabetic rats demonstrating just slight thickening of basement membrane, b glomerular basement membrane thickening (GBMT) and c mesangial fractional volume (Vv (mes/glom)), data are presented as the mean of 10 glomeruli from 4 animals ± SD. ...
Article
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Deregulated activity of protein kinase B/mammalian target of rapamycin complex-1 (Akt/mTORC1) incites crucial pathological characteristics of diabetic nephropathy. The acyclic monoterpene geraniol has been recently reported to possess antidiabetic effects; however, its potential renoprotective effect in diabetes has not yet been elucidated. This study aimed to assess the possible modulatory effect of geraniol on the Akt/mTORC1 pathway in diabetes-induced nephropathy in rats compared to the standard antidiabetic drug gliclazide. Geraniol and gliclazide was administered daily to diabetic rats for 6 weeks starting on the 3rd-day post diabetes induction by streptozotocin (STZ). Geraniol amended the deteriorated renal function (serum creatinine; blood urea nitrogen). It exerted a remarkable antihyperglycemic effect that is comparable to that of gliclazide and suppressed the fibrotic marker, transforming growth factor-β. Geraniol restored redox balance and inhibited lipid peroxidation by reducing nicotine amide adenine dinucleotide phosphate oxidase and enhancing the antioxidant enzyme, superoxide dismutase. These beneficial effects were associated with a robust downregulation of miRNA-21 and consequently, reversion of tumor suppressor protein phosphatase and tension homolog (PTEN)/Akt/mTORC1 cue and its downstream proteins required for mesangial cell proliferation and matrix protein synthesis. The current study indicates that geraniol interfered with miRNA-21/ PTEN/AKT/mTORC1 pathway signaling that contributes largely to the progression of mesangial expansion and extracellular matrix deposition in diabetic nephropathy.
... PA treatment alleviated this deficit to some extent, reducing escape latency significantly, but had no significant effect on total time taken to cross the beam, even though a decreasing trend was observed in treated animals. Our results are consistent with previous reports of monoterpenes attenuating behavioural impairments and restoring motor function in a murine model of neuropathy (Prasad and Muralidhara 2014). ...
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In this study, we aim to assess the phytomedicinal potential of perillyl alcohol (PA), a dietary monoterpenoid, in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson’s disease (PD). We observed that PA supplementation alleviated behavioural abnormalities such as loss of coordination, reduced rearing and motor asymmetry in lesioned animals. We also observed that PA-treated animals exhibited reduced oxidative stress, DNA fragmentation and caspase 3 activity indicating alleviation of apoptotic cell death. We found reduced mRNA levels of pro-apoptotic regulator BAX and pro-inflammatory mediators IL18 and TNFα in PA-treated animals. Further, PA treatment successfully increased mRNA and protein levels of Bcl2, mitochondrial biogenesis regulator PGC1α and tyrosine hydroxylase (TH) in lesioned animals. We observed that PA treatment blocked BAX and Drp1 translocation to mitochondria, an event often associated with the inception of apoptosis. Further, 6-OHDA exposure reduced expression of electron transport chain complexes I and IV, thereby disturbing energy metabolism. Conversely, expression levels of both complexes were upregulated with PA treatment in lesioned rats. Finally, we found that protein levels of Nrf2, the transcription factor responsible for antioxidant gene expression, were markedly reduced in cytosolic and nuclear fraction on 6-OHDA exposure, and PA increased expression of Nrf2 in both fractions. We believe that our data hints towards PA having the ability to provide cytoprotection in a hemiparkinsonian rat model through alleviation of motor deficits, oxidative stress, mitochondrial dysfunction and apoptosis.
... Wang et al. [44] stated that at a dose of 250 mg kg -1 geraniol can reduce oxidative stress by reducing lipid peroxidation and affecting the activity of GSH and other antioxidant enzymes. Prasad and Muralidhara [45] have also suggested that geraniol can be a promising antioxidant by reducing oxidative stress. Pb acetate + Geraniol 7 262 ± 2 * * : p < 0.05 compared with the control group ...
... It has also been demonstrated in an in vitro study that nutmeg lignans and their glycosides are metabolized after absorption to produce biologically active compounds containing catechol structure, which accounts for the high antioxidant potential of the nutmeg [61]. Geraniol is a monoterpene found in nutmeg and has been demonstrated to correct the biochemical abnormalities associated with diabetic neuropathy in diabetic rats [65]. ...
Article
Background Diabetes mellitus type-II is a major health problem characterized by hypo-insulinemia and insulin resistance; leading to hyperglycemia and its complications. In Unani medicine, it is known as ziyābetus. Several drugs are prescribed in Unani medicine as single and compound formulations for this disease. Most of these drugs have been studied on scientific parameters and shown significant activity in reducing the symptoms and complications of diabetes. Objectives Critical evaluation of Unani medicines for treating diabetes patients. To provide complete information on this subject with the action of the mechanism so that proper treatment should be done with prospective research. Methods Unani literature was reviewed extensively via various search engines for the herbs, shrubs used for diabetes treatment. Ten drugs were selected for the present review. Results and Conclusion There is convincing evidence to suggest that the selected drugs have promising actions against diabetes and its complications. Also, none of the studies has reported any adverse effects with the drugs. Also, there is evidence to suggest that the method of usage described in Unani medicine may reduce or eliminate adverse events if any. Further, there is a great need to do more research on making medicine more effective. Besides, the review article is useful for treating patients effectively by advancing the research.
... Geraniol exerts protective activity for both the gastric and duodenal mucosa [18], it is antioxidant and cytoprotective [19], anti-inflammatory [20], acts as a chemopreventive in colon [21,22], pancreatic [23], and kidney cancers [24], and has in vivo anti-tumour action against murine leukaemia, hepatocellular carcinoma and melanoma [25][26][27]. In a study conducted by Prasad and Muralidhara [28] geraniol showed neuroprotective effects, tested in induced diabetic neuropathy model in rodents. Additionally, geraniol exerts negative inotropic and chronotropic actions in mammalian myocardiocytes, decreasing the ion currents in both Ltype Ca 2+ and K + voltage-dependent channels, ultimately acting with anti-arrhythmic potential [29]. ...
Article
Geraniol (GER) is a monoterpene alcohol with various biochemical and pharmacological properties present in the essential oil of more than 160 species of herbs, (especially the Cymbopogon genus). In this study, we evaluated the anti-nociceptive activity of GER in behavioural and electrophysiological in vitro experimental models of nociception using male Swiss mice. GER (12.5, 25 or 50 mg/kg i.p. and 50 or 200 mg/kg p.o.) reduced the number of writhes induced by acetic acid. The opioid antagonist naloxone (5 mg/kg s.c.) administered in mice subsequently treated with GER (25 mg/kg i.p.) did not reverse such anti-nociceptive activity, suggesting a non-opioid pathway for the mechanism of action. GER (12.5, 25 and 50 mg/kg i.p.) reduced paw licking time in the second phase of the formalin test. Also, in the glutamate test, GER when administered 50 mg/kg i.p. reduced paw licking time, probably modulating glutamatergic neurotransmission. GER blocked reversibly components of the compound action potential (CAP) recorded in isolated sciatic nerve in a dependent manner for concentration and drug exposure time: 1 mM to 120 min. for the first component and 0.6 mM to 90 min. for the second component. The IC50 was calculated for the peak-to-peak amplitude (PPA) at 0.48 ± 0.04 mM. The conduction velocity was also reduced by exposure to GER starting from the concentration of 0.3 mM for both components of the CAP. In conclusion, it is suggested that GER has anti-nociceptive activity, especially in pain related to inflammation, and in part related to reduced peripheral nerve excitability. This article is protected by copyright. All rights reserved.
... Recently, Wang et al. (2016) reported that geraniol (250 mg/kg) reduces the serum MDA and increases the GSH and glutathione peroxidase in rats. Prasad and Muralidhara (2014) also revealed that this monoterpene may be a promising therapeutic candidate that acts by reducing the oxidative stress. They used highdose geraniol compared to our experiment. ...
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In this study, the effect of geraniol (50 mg/kg for 30 d), a natural antioxidant and repellent/antifeedant monoterpene, in a rat model of lead acetate-induced (500 ppm for 30 d) liver damage was evaluated. Hepatic malondialdehyde increased in the lead acetate group. Reduced glutathione unchanged, but glutathione S-transferase, glutathione reductase, as well as carboxylesterase activities decreased in geraniol, lead acetate and geraniol + lead acetate groups. 8-OhDG immunoreactivity, mononuclear cell infiltrations and hepatic lead concentration were lower in the geraniol + lead acetate group than the lead acetate group. Serum aspartate aminotransferase and alanine aminotransferase activities increased in the Pb acetate group. In conclusion, lead acetate causes oxidative and toxic damage in the liver and this effect can reduce with geraniol treatment. However, we first observed that lead acetate, as well as geraniol, can affect liver carboxylesterase activity.
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Eugenol (EU), an active principle of cloves, is also widely distributed in various other plants (eg. basil, cinnamon etc). While its antioxidant and anti-inflammatory properties are well established, biochemical insights related to its neuromodulatory potential in diabetic conditions are not clear. In the present study, initially we investigated its potential to modulate specific biochemical responses in SH-SY5Y cells under experimentally -induced hyperglycemic condition. Co-exposure of cells with EU (5 - 10 μM) not only enhanced the cell viability, but significantly offset glucose -associated oxidative stress (as evidenced by diminished levels of reactive oxygen species and hydroperoxides). Further EU enhanced the reduced glutathione (GSH) levels and also ameliorated the levels of 3 - nitrotyrosine and expression of HSP70. We subsequently examined its efficacy to attenuate biochemical aberrations in brain regions of a streptozotocin (STZ) diabetic rat employing an intervention approach. Brain regions of EU treated (10 mg/kg bw/d, post 6 weeks of STZ) diabetic rats showed diminished levels of oxidative markers and protein carbonyls in both cytosolic and mitochondrial fractions. EU treatment caused enhanced activities of enzymic antioxidants and diminished both GSH and total thiols. Further, activities of complex I - III, succinate dehydrogenase and citrate synthase in brain regions were also significantly restored. Interestingly, EU treatment differentially attenuated the elevated activity of acetylcholinesterase and levels of calcium in brain regions. Collectively, based on the data obtained in in vitro and in vivo models, we hypothesize that EU may be employed as an adjuvant therapeutic molecule to alleviate complications under diabetic conditions.
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Ulcerative colitis is associated with a considerable reduction in the quality of life of the patients. The use of phyto-ingredients is becoming an increasingly attractive approach for the management of colitis. Geraniol, a monoterpene with anti-inflammatory and antioxidative properties. In this study, we investigated the therapeutic potential of geraniol as complementary and alternative medicine against dextran sulphate sodium (DSS)-induced ulcerative colitis in mice. Disease activity indices (DAI) comprising body weight loss, presence of occult blood and stool consistency were assessed for evaluation of colitis symptoms. Intestinal damage was assessed by evaluating colon length and its histology. Pre-treatment with geraniol significantly reduced DAI score, improved stool consistency (without occult blood) and increased the colon length. The amount of pro-inflammatory cytokines, specifically TNF-α, IL-1β and IL-6 and the activity of myeloperoxidase in colon tissue were significantly decreased in geraniol pre-treated mice. Western blot analyses revealed that geraniol interfered NF-κB signaling by inhibiting NF-κB (p65)-DNA binding, IκBα phosphorylation and its degradation and subsequent increase in nuclear translocation. Moreover, the expression of downstream target pro-inflammatory enzymes such as iNOS and COX-2 were significantly reduced by geraniol. Pre-treatment with geraniol also restored the DSS-induced decline in antioxidant parameters such as reduced glutathione and superoxide dismutase activity and attenuated the increase in lipid peroxidation marker, thiobarbituric acid reactive substances and nitrative stress marker, nitrites in colon tissue. Thus, our results suggest that geraniol is a potential therapeutic agent for inflammatory bowel disease.
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During dry seasons or years, the runoff processes from small rivers influence the safety of riverside groundwater source fields. Water source exploitation has a considerable effect on river runoff. In this study, the riverside source field of the Liuan River in the Linquan County, Anhui Province, was analyzed. The effect of mining on the ecological flow of the river under river runoff conditions in different typical dry years was quantified. This was undertaken using numerical simulations of the groundwater flow to provide guidance for the establishment of mining schemes for riverside source fields. In 95% of typical dry years, the water supply of small rivers is insufficient. The improved 7Q10 method used to calculate the ecological flow in different dry years revealed that mining water had little effect on the ecological flow. However, during the pumping process, the groundwater level of the water source area decreased greatly. The establishment of riverside source fields can aid in reducing excessive development and use of deep groundwater. The planning, construction, and implementation of the “Divert water from the Yangtze River to the Huaihe River” project can effectively reduce the economic losses that have occurred due to severe drought in the local area.
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Geraniol, a plant derived monoterpene, has been extensively studied and showed a wide variety of beneficial effects. The aim of this study was to investigate the therapeutic effect of geraniol on functional recovery and neuropathic pain in rats with spinal cord injury (SCI). Rats received a clip-compression SCI and were treated with geraniol 6 hours following SCI. Treatment of SCI rats with geraniol markedly improved locomotor function, and reduced sensitivity to the mechanical allodynia and thermal hyperalgesia. Treatment of SCI rats with geraniol increased NeuN-positive cells, suppressed expression of glial fibrillary acidic protein, and reduced activity of caspase-3 in injured region. Treatment of SCI rats with geraniol reduced levels of malondialdehyde and 3-nitrotyrosine, upregulated protein expression of nuclear factor-erythroid 2-related factor 2 and heme oxygenase 1, and suppressed expression of inducible nitric oxide synthase in the injured region. In addition, treatment of SCI rats with geraniol downregulated protein expression of N-methyl-D-aspartate receptor 1 and reduced number of CD68-positvie cells and protein levels of TNF-α in the injured region. In conclusions, geraniol significantly promoted the recovery of neuronal function and attenuated neuropathic pain after SCI.
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Staphylococcal infections associated with indwelling medical devices are difficult to eradicate owing to its recalcitrant nature of biofilms to conventional antibiotics. In our earlier study, we reported the efficacy of geraniol (GE) in inhibiting the in vitro biofilm formation of S. epidermidis and adaptive resistant development. To examine the in vivo potential of GE in eradicating the in vivo colonization of S. epidermidis, an implanted rat jugular vein catheter model was developed. Oral supplementation of GE (GE at 200 mg/kg bw for three days) in rats infected with S. epidermidis exhibited a significant reduction of the bacterial burden in catheter, blood, heart and kidney, when compared to the untreated infection control. In addition, GE supplemented animals showed significantly reduced level of inflammatory markers such as nitric oxide and malondialdehyde in heart and kidney tissues. Furthermore, in contrast to the infection control, histopathology analysis of the heart and kidney tissues of the GE treated group showed a normal histoarchitecture similar to animal control. Thus, the outcome of the present study exhibits the potential of GE as antibiofilm and anti-inflammatory agent against S. epidermidis infections. Further, elucidating the molecular mechanism of GE is important to exploit the therapeutic efficacy of GE.
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Growing evidence indicates links between type 2 diabetes and Parkinson's disease. The glucagon-like peptide 1 analogue, liraglutide, a commonly used anti-diabetic drug, has protective effects on neurons. The goal of this study was to determine whether long-term liraglutide treatment could reduce the risk of adult type 2 diabetic mice developing Parkinson's disease. Male diabetic db/db mice (12 weeks old) were injected daily with liraglutide (n = 8), or saline (n = 8), and non-diabetic m/m littermates (n = 6) were included as controls. Motor function was assessed every 4 weeks and all mice were sacrificed after 8 weeks of drug intervention for further analysis. The results revealed that long-term treatment of liraglutide protected the db/db mice against the motor function decay and the dopaminergic neuron loss. Liraglutide also restored the impaired AMP kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator 1a (PGC-1a) signaling in the striatum of db/db mice. Further experiments in SH-SY5Y cells supported that AMPK is involved in the neuroprotective effect of liraglutide. In summary, long-term liraglutide ameliorated motor dysfunction and dopaminergic neuron impairment in type 2 diabetic mice, probably via enhancing AMPK/PGC-1a signaling.
Chapter
Terpenoids are volatile compounds synthetized and secreted by several organisms, in particularly by medicinal plants as secondary metabolites. These phytochemical compounds have shown several benefits in healthcare by their numerous pharmacological properties. Indeed, they have antibacterial, antifungal, antioxidant, antiviral, anticancer, and antidiabetic effects. Biological activities of terpenoids are related to their capacity to exert several mechanism insights. In this chapter, the pharmacological activities of terpenoids and their mechanism insights were explored and discussed.
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Aims Zinc oxide nanoparticles (ZnO-NPs) are currently applied in food and pharmaceutical industries whose neurotoxic effect on the central nervous system (CNS) is a major concern. Considering the pharmacological properties (antioxidant, anti-inflammatory) of the geraniol (GE), we aimed to investigate the efficacy of geraniol on ZnO-NPs neurotoxicity. Materials and methods We used 32 male Wistar rats, randomly assigned to four groups (n = 8): Control, GE (daily received 100 mg/kg of GE by gavage), ZnO-NPs (received intraperitoneal injection of 75 mg/kg of ZnO-NPs twice a week), and ZnO-NPs + GE (received both GE and ZnO-NPs at same doses above during 4 weeks). Morris water maze (MWM) and Y-maze tasks were done to evaluate learning and memory function. Biochemical assays were done to measure total antioxidant capacity (TAC), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX) and ZnO-NPs bioaccumulation. Nissl and H&E staining were performed for histological evaluations. Key findings The results of behavioral study revealed that GE improved learning and memory impairment induced by ZnO-NPs. Moreover, neuroprotective effect of GE significantly decreased pathological parameters such as necrosis and gliosis, and consequently increased the number of nerve cells in the cortex and different hippocampal areas. Furthermore, biochemical studies demonstrated that GE significantly increased antioxidant indices (namely, TAC, SOD, and GPX) and reduced oxidative stress marker (MDA) and Zn bioaccumulation in ZnO-NPs treated animals. Significance Our results provide experimental evidence to further investigate the precise mechanisms underlying the geraniol as a promising therapeutic approach for improvement of cognitive function and neurotoxicity induce by ZnO-NPs.
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There is accumulating evidence that showing oxidative stress plays a critical role in the progression of diabetes. It was reported that geraniol, as monoterpenoid alcohol, has antioxidant properties. This study aimed to investigate the effect of geraniol on serum lipid parameters and antioxidant defense systems in the pancreas, liver, and heart tissues of alloxan-induced diabetic rats. Forty albino wistar rats were randomly divided into five groups, including (I) control group, (II) diabetic group, (III) the diabetic group treated with glibenclamide, (IV) the diabetic group treated with 200 mg/kg geraniol, and (V) the diabetic group receiving the geraniol solvent for four weeks. At the end of treatment, serum glucose level, lipid profile (TG, TC, LDL, and HDL), liver aminotransferases (ALT, AST), and ALP activities in different groups were measured. Furthermore, malondialdehyde (MDA) content, as a lipid peroxidation marker, the activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) enzymes were assessed in pancreas, liver, and heart tissues of different groups. The result indicated that treatment with geraniol decreased fasting blood glucose, HbA1c, triglyceride, total cholesterol, and LDL-cholesterol, whereas the blood high-density lipoprotein -cholesterol level was elevated. In addition, treatment of diabetic rats with geraniol increased the activity of GPx and SOD antioxidant enzymes and decreased the MDA content as a marker of lipid peroxidation in the pancreas, liver, and heart tissues as compared to the diabetic rats. Due to the high potential of geraniol in lowering blood sugar and oxidative parameters in the various tissues of diabetic rats, the antioxidant property of geraniol is the most likely mechanism for its hypoglycemic effect.Graphical abstract
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The present study aimed to analyze age-related changes to motor coordination, balance, spinal cord oxidative biomarkers in 3-, 6-, 18-, 24-, and 30-month-old rats. The effects of low-intensity exercise on these parameters were also analyzed in 6-, 18-, and 24-month-old rats. Body weight, blood glucose, total cholesterol, and high-density lipoprotein (HDL) cholesterol were assessed for all rats. The soleus muscle weight/body weight ratio was used to estimate skeletal muscle mass loss. Body weight increased until 24 months; only 30-month-old rats exhibited decreased blood glucose and increased total cholesterol and HDL cholesterol. The soleus muscle weight/body weight ratio increased until 18 months, followed by a small decrease in old rats. Exercise did not change any of these parameters. Stride length and step length increased from adult to middle age, but decreased at old age. Stride width increased while the sciatic functional index decreased in old rats. Performance in the balance beam test declined with age. While gait did not change, balance improved after exercise. Aging increased superoxide anion generation, hydrogen peroxide levels, total antioxidant capacity, and superoxide dismutase activity while total thiol decreased and lipid hydroperoxides did not change. Exercise did not significantly change this scenario. Thus, aging increased oxidative stress in the spinal cord, which may be associated with age-induced changes in gait and balance. Regular low-intensity exercise is a good alternative for improving age-induced changes in balance, while beneficial effects on gait and spinal cord oxidative biomarkers cannot be ruled out because of the small number of rats investigated (n=5 or 6/group).
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Many reports have been published about the biogenesis of silver nanoparticles using several plant extracts such as Pelargonium graveolens (P.graveolens- geranium) and Azadirachta indica (neem) but the capacity of their natural reducing constituents to form silver nanoparticles has not yet been studied. In this research the synthesis of silver nanoparticles using geraniol has been investigated. We successfully synthesized uniformly dispersed silver nanoparticles with a uniform size and shape in the range of 1 to 10 nm with an average size of 6 nm. Also the cytotoxicity of the prepared silver nanoparticles was investigated using a cancer cell line (Fibrosarcoma-Wehi 164). The cytotoxicity analysis of the sample shows a direct dose-response relationship; cytotoxicity increased at higher concentrations. At concentration of 1 µg/ml, silver nanoparticles was able to inhibit the cell line's growth by less than 30%. Conversly, the presence of 5 µg/ml of silver nanoparticlse significantly inhibited the cell line's growth (>60%). The concentration necessary to produce 50% cell death was 2.6 µg/ml for this silver nanoparticles preapared with geraniol.
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Many reports have been published about the biogenesis of silver nanoparticles using several plant extracts such as Pelargonium graveolens (P.graveolens-geranium) and Azadirachta indica (neem) but the capacity of their natural reducing constituents to form silver nanoparticles has not yet been studied. In this research the synthesis of silver nanoparticles using geraniol has been investigated. We successfully synthesized uniformly dispersed silver nanoparticles with a uniform size and shape in the range of 1 to 10 nm with an average size of 6 nm. Also the cytotoxicity of the prepared silver nanoparticles was investigated using a cancer cell line (Fibrosarcoma-Wehi 164). The cytotoxicity analysis of the sample shows a direct dose-response relationship; cytotoxicity increased at higher concentrations. At concentration of 1 μg/ml, silver nanoparticles was able to inhibit the cell line's growth by less than 30%. Conversly, the presence of 5 μg/ml of silver nanoparticlse significantly inhibited the cell line's growth (> 60%). The concentration necessary to produce 50% cell death was 2.6 μg/ml for this silver nanoparticles preapared with geraniol.
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The primary objective of this investigation was to assess the neuroprotective efficacy of spice active principles namely Eugenol (Eug) and isoeugenol (IE) in an acrylamide (ACR) neuropathy model in rats. In the present study, ACR administration (50 mg/kg bw, i.p. 3 times/week) for 5 weeks to growing rats caused typical symptoms of neuropathy. We found that treatment of ACR rats with spice active principles (10 mg/kg bw, for 5 weeks) caused marked improvement in gait score and responses in a battery of behavioral tests. Terminally, both spice active principles markedly attenuated ACR-induced markers of oxidative stress viz., reactive oxygen species (ROS), malondialdehyde (MDA) and nitric oxide (NO) in sciatic nerve (SN) as well as brain regions (cortex Ct, cerebellum Cb). Treatment with Eug restored the reduced glutathione levels in SN and brain regions. Interestingly, both spice active principles effectively diminished ACR-induced elevation in cytosolic calcium levels and acetylcholinesterase activity in SN and Ct. Further, the diminished activity of ATPase among ACR rats was enhanced in SN and restored in brain regions. Furthermore, Eug treatment significantly offset ACR-induced depletion in dopamine levels in brain regions. Collectively our findings suggest the propensity of these spice active principles to attenuate ACR-induced neuropathy. Further studies are necessary to understand the precise molecular mechanism/s by which these spice active principles attenuate neuropathy. Nevertheless, our data clearly demonstrate the beneficial effects of spice active principles in ACR-induced neuropathy in rats and suggest their possible therapeutic usage as an adjuvant in the management of other forms of neuropathy in humans.
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Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P
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In the present study, we have evaluated the chemopreventive potential of geraniol (GOH), an acyclic monoterpene alcohol against ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and carcinogenesis in Wistar rats. Chronic treatment of Fe-NTA induced oxidative stress, inflammation and cellular proliferation in Wistar rats. The chemopreventive efficacy of GOH was studied in terms of xenobiotic metabolizing enzyme activities, LPO, redox status, serum toxicity markers and the expression of putative nephrotoxicity biomarker Kim-1, tumor suppressor gene P53, inflammation, cell proliferation and apoptosis related genes in the kidney tissue. Oral administration of GOH at doses of 100 and 200mg/kg b wt effectively suppressed renal oxidative stress and tumor incidence. Chemopreventive effects of GOH were associated with upregulation of xenobiotic metabolizing enzyme activities and down regulation of serum toxicity markers. GOH was able to down regulate expression of Kim-1, NFκB, PCNA, P53 along with induction of apoptosis. However, higher dose of GOH was more effective in modulating these multiple molecular targets both at transcriptional and protein level. These results provide a powerful evidence for the chemopreventive efficacy of GOH against renal carcinogenesis possibly by modulation of multiple molecular pathways.
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Diabetic neuropathy is a major complication of diabetes that affects the sensory and autonomic nervous systems and leads to significant morbidity and impact on quality of life of patients. Mitochondrial stress has been proposed as a major mediator of neurodegeneration in diabetes. This review briefly summarizes the nature of sensory and autonomic nerve dysfunction and presents these findings in the context of diabetes-induced nerve degeneration mediated by alterations in mitochondrial ultrastructure, physiology and trafficking. Diabetes-induced dysfunction in calcium homeostasis is discussed at length and causative associations with sub-optimal mitochondrial physiology are developed. It is clear that across a range of complications of diabetes that mitochondrial physiology is impaired, in general a reduction in electron transport chain capability is apparent. This abnormal activity may predispose mitochondria to generate elevated reactive oxygen species (ROS), although experimental proof remains lacking, but more importantly will deleteriously alter the bioenergetic status of neurons. It is proposed that the next five years of research should focus on identifying changes in mitochondrial phenotype and associated cellular impact, identifying sources of ROS in neurons and analyzing mitochondrial trafficking under diabetic conditions.
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Morbid obesity may be accompanied by diabetes and painful diabetic neuropathy, a poorly understood condition that is manifested by mechanical or thermal allodynia and hyperalgesia. Recent studies have highlighted the importance of T-type calcium channels (T-channels) in peripheral nociception; therefore, our goal was to examine the function of these channels in the pathophysiology and development of painful diabetic neuropathy. In vivo testing of mechanical and thermal sensation, morphometric peripheral nerve studies, and electrophysiological and biochemical measurements were used to characterize the role of T-channels and the development of painful diabetic neuropathy in leptin-deficient (ob/ob) mice. We found that ob/ob mice developed significant mechanical and thermal hypersensitivity early in life that coincided with hyperglycemia and was readily reversed with insulin therapy. These disturbances were accompanied by significant biophysical and biochemical modulation of T-channels in dorsal root ganglion neurons as measured by a large increase in the amplitude of T-currents and the expression of mRNA. The most prevalent subtype, alpha1H (Ca(v)3.2), was most strongly affected. Moreover, (3beta,5alpha,17beta)-17-hydroxyestrane-3-carbonitrile (ECN), a novel neuroactive steroid and selective T-channel antagonist, provided dose-dependent alleviation of neuropathic thermal and mechanical hypersensitivity in diabetic ob/ob mice. Our results indicate that pharmacological antagonism of T-channels is potentially an important novel therapeutic approach for the management of painful diabetic neuropathy.
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Uncontrolled diabetes is known to affect the nervous system. The aim of this study was to investigate the effect of the antioxidant L: -cysteine (Cys) on the changes caused by adult-onset streptozotocin (STZ)-induced diabetes on the rat brain total antioxidant status (TAS) and the activities of acetylcholinesterase (AChE), (Na(+),K(+))-ATPase and Mg(2+)-ATPase. Thirty-eight male Wistar rats were divided into six groups: C(A) (8-week-control), C(B) (8-week-control + 1-week-saline-treated), C + Cys (8-week-control + 1-week-Cys-treated), D(A) (8-week-diabetic), D(B) (8-week-diabetic + 1-week-saline-treated) and D + Cys (8-week-diabetic + 1-week-Cys-treated). All diabetic rats were once treated with an intraperitoneal (i.p.) STZ injection (50 mg/kg body weight) at the beginning of the experiment, while all Cys-treated groups received i.p. injections of Cys 7 mg/kg body weight (daily, for 1-week, during the 9th-week). Whole rat brain parameters were measured spectrophotometrically. In vitro incubation with 0.83 mM of Cys or 10 mM of STZ for 3 h was performed on brain homogenate samples from groups C(B) and D(B), in order to study the enzymes' activities. Diabetic rats exhibited a statistically significant reduction in brain TAS (-28%, D(A) vs C(A);-30%, D(B) vs C(B)) that was reversed after 1-week-Cys-administration into basal levels. Diabetes caused a significant increase in AChE activity (+27%, D(A) vs C(A); +15%, D(B) vs C(B)), that was further enhanced by Cys-administration (+57%, D + Cys vs C(B)). The C + Cys group exhibited no significant difference compared to the C(B) group in TAS (+2%), but showed a significantly increased AChE activity (+66%, C + Cys vs C(B)). Diabetic rats exhibited a significant reduction in the activity of Na(+),K(+)-ATPase (-36%, D(A) vs C(A);-48%, D(B) vs C(B)) that was not reversed after 1-week Cys administration. However, in vitro incubation with Cys partially reversed the diabetes-induced Na(+),K(+)-ATPase inhibition. Mg(2+)-ATPase activity was not affected by STZ-induced diabetes, while Cys caused a significant inhibition of the enzyme, both in vivo (-14%, C + Cys vs C(B);-17%, D + Cys vs C(B)) and in vitro (-16%, D(B) + in vitro Cys vs C(B)). In vitro incubation with STZ had no effect on the studied enzymes. The present data revealed a protective role for Cys towards the oxidative effect of diabetes on the adult rat brain. Moreover, an increase in whole brain AChE activity due to diabetes was recorded (not repeatedly established in the literature, since contradictory findings exist), that was further increased by Cys. The inhibition of Na(+),K(+)-ATPase reflects a possible mechanism through which untreated diabetes could affect neuronal excitability, metabolic energy production and certain systems of neurotransmission. As concerns the use of Cys as a neuroprotective agent against diabetes, our in vitro findings could be indicative of a possible protective role of Cys under different in vivo experimental conditions.
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Bioactive food components (BFACs) represent promising candidates for liver cancer chemoprevention. Among them, isoprenic derivatives (carotenoids, retinoids, perillyl alcohol, limonene, geraniol, farnesol, geranylgeraniol and β- ionone) can be highlighted. The relevance of animal models for the investigation of chemopreventive agents is supported by comparative functional genomic studies that reinforce the similarities between rodent and human hepatocarcinogenesis. Thus, characterization of BFACs in animal models as blocking and/or suppressing agents allows the establishment of the theoretical basis for the development of chemoprevention strategies. Dietary isoprenic derivatives actions on hepatocarcinogenesis may involve a block in carcinogen activation, induction of phase 2 enzymes and an antioxidant activity, as well as interference with cellular processes including cell communication, proliferation, apoptosis, differentiation and remodeling of preneoplastic lesions. Dietary isoprenic derivatives modulate molecular targets including HMG-CoA-reductase, Rho, nuclear receptors, c-myc, connexin 43, NF-κB and Nrf2. Several networks related to these targets are altered in early phases of hepatocarcinogenesis. This emphasizes the importance of such agents for the chemoprevention of hepatocellular carcinoma. Combinations of isoprenic derivatives or of these substances with other BFACs classes should be further investigated. Also, toxicity and bioavailability and pharmacokinetic aspects of these derivatives represent relevant issues in their development as chemopreventive agents. One major current limitation of the adoption of dietary isoprenic derivatives for liver cancer chemoprevention is the challenge in overcoming the initial preclinical phase in agent development. Dietary isoprenic derivatives that present liver cancer chemopreventive properties should be further explored in clinical trials, begining with the phase 0 approach.
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Publisher Summary This chapter is dedicated to describing citrate synthase. The assay of citrate synthase is performed by coupling it to the transacetylase reaction. The disappearance of acetyl phosphate is followed by a hydroxamate method and the formation of citrate by the pentabromoacetone method. The malate dehydrogenase catalyzed reaction is used to generate the oxaloacetate for the citrate synthase reaction. Another method for assaying citrate synthase uses 14 C-acetyl-CoA and measures its incorporation in 14 C-citrate, which is isolated as a silver salt. Citrate synthase can be followed by measuring the appearance of the free SH group of the released CoASH; three such methods are discussed in the chapter. One method is to measure the oxidation of the CoASH by dichlorophenol- indophenol, which is accompanied by a decrease in absorbancy at 578 mμ. Another method measures the CoASH polarographically. The third method measures SH by the use of 5, 5’-dithiobis-(2-nitrobenzoate) (DTNB) (Ellman's reagent).
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a b s t r a c t Parkinson's disease (PD) is characterized by progressive loss of dopamine (DA) neurons in the nigrostri-atal system and by the presence of Lewy bodies (LB), proteinaceous inclusions mainly composed of fila-mentous a-synuclein (a-Syn) aggregates. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was adopted to generate PD models in C57BL/6 mice. In the present study, we investigated the effect of gera-niol (GE) against a-Syn aggregation on MPTP induced mouse model of PD in dose dependant manner. When pretreatment of GE improved neuromuscular impairment, TH expressions and decreases a-Syn expressions in MPTP intoxicated PD mice by dose dependent manner. In addition, we confirmed that sub-chronic administration of MPTP in mice leads to permanent neuromuscular deficits and depletion of dopamine and its metabolites. Our results suggest that GE is beneficial for the treatment of PD asso-ciated with neuromuscular disability and LB aggregation.
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Chronic exposure of acrylamide (ACR) leads to neuronal damage in both experimental animals and humans. The primary focus of this study was to assess the ameliorative effect of geraniol, (a natural monoterpene) against ACR-induced oxidative stress, mitochondrial dysfunction and neurotoxicity in a Drosophila model and compare its efficacy to that of curcumin, a spice active principle with pleiotropic biological activity. Adult male flies (8-10 d) were exposed (7 d) to ACR (5mM) with or without geraniol and curcumin (5-10μM) in the medium. Both phytoconstituents significantly reduced the incidence of ACR -induced mortality, rescued the locomotor phenotype and alleviated the enhanced levels of oxidative stress markers in head/body regions. The levels of reduced glutathione (GSH) and total thiols (TSH) resulting from ACR exposure was also restored with concomitant elevation in the activities of detoxifying enzymes. Interestingly, ACR induced mitochondrial dysfunctions (MTT reduction, activities of SDH and citrate synthase enzymes) were alleviated by both phytoconstituents. While ACR elevated the activity of acetylcholinesterase in head/body regions, marked diminution in enzyme activity ensued with co-exposure to phytoconstituents suggesting their potency to mitigate cholinergic function. Furthermore, phytoconstituents also restored the dopamine levels in head/ body regions. The neuroprotective effect of geraniol was comparable to curcumin in terms of phenotypic and biochemical markers. Based on our evidences in fly model we hypothesise that geraniol possess significant neuromodulatory propensity and may be exploited for therapeutic application in human pathophysiology associated with neuropathy. However, the precise mechanism/s by which geraniol offers neuroprotection needs to be investigated in appropriate neuronal cell models.
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Diabetes mellitus, a debilitating chronic disease, affects ~100 million people. Peripheral neuropathy is one of the most common early complications of diabetes in ~66 % of these patients. Altered Ca2+ handling and Ca2+ signaling were detected in a huge variety of preparations isolated from animals with experimentally induced type 1 and 2 diabetes as well as patients suffering from the disease. We reviewed the role of Ca2+ signaling through cation channels and oxidative stress on diabetic neuropathic pain in sensory neurons. The pathogenesis of diabetic neuropathy involves the polyol pathway, advanced glycation end products, oxidative stress, protein kinase C activation, neurotrophism, and hypoxia. Experimental studies with respect to oxidative stress and Ca2+ signaling, inhibitor roles of antioxidants in diabetic neuropathic pain are also summarized in the review. We hypothesize that deficits in insulin, triggers alterations of sensory neurone phenotype that are critical for the development of abnormal Ca2+ homeostasis and oxidative stress and associated mitochondrial dysfunction. The transient receptor potential channels are a large family of proteins with six main subfamilies. The sheer number of different TRPs with distinct functions supports the statement that these channels are involved in a wide range of processes ranging in diabetic neuropathic pain and it seems that the TRPC, TRPM and TRPV groups are mostly responsible from diabetic neuropathic pain. In conclusion, the accumulating evidence implicating Ca2+ dysregulation and over production of oxidative stress products in diabetic neuropathic pains, along with recent advances in understanding of genetic variations in cation channels such as TRP channels, makes modulation of neuronal Ca2+ handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many diabetic neuropathies.
Article
Parkinson's disease (PD) is characterized by progressive loss of dopamine (DA) neurons in the nigrostriatal system and by the presence of Lewy bodies (LB), proteinaceous inclusions mainly composed of filamentous α-synuclein (α-Syn) aggregates. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was adopted to generate PD models in C57BL/6 mice. In the present study, we investigated the effect of geraniol (GE) against α-Syn aggregation on MPTP induced mouse model of PD in dose dependant manner. When pretreatment of GE improved neuromuscular impairment, TH expressions and decreases α-Syn expressions in MPTP intoxicated PD mice by dose dependent manner. In addition, we confirmed that sub-chronic administration of MPTP in mice leads to permanent neuromuscular deficits and depletion of dopamine and its metabolites. Our results suggest that GE is beneficial for the treatment of PD associated with neuromuscular disability and LB aggregation.
Article
Geraniol is a commercially important terpene alcohol occurring in the essential oils of several aromatic plants. It is one of the most important molecules in the flavour and fragrance industries and is a common ingredient in consumer products produced by these industries. In addition to its pleasant odour, geraniol is known to exhibit insecticidal and repellent properties and used as a natural pest control agent exhibiting low toxicity. Geraniol has been suggested to represent a new class of chemoprevention agents for cancer. Other biological activities such as antimicrobial, anti-oxidant, anti-inflammatory and some vascular effects have also been investigated. The effect of geraniol as a penetration enhancer for transdermal drug delivery has also attracted the attention of researchers and formulation scientists. This review aims to coherently discuss some of the most important applications of geraniol and unites the results obtained from several studies reporting the biological properties of this molecule.
Article
Publisher Summary Hydroperoxides in biological systems can be measured by electroanalytical determination using high-performance liquid chromatography (HPLC), chemiluminescence using microperoxidase-luminol, activation of cyclooxygenase, techniques based on thiobarbituric acid (TBA) conjugation of malonaldehyde, iodide oxidation: conjugated diene formation, and alkane expiration. Of these, the TBA methods are most widely used. They require the least sophisticated instrumentation, but they are the most criticized on grounds of their ambiguity. This chapter describes two simple and sensitive spectrophotometric methods that have the advantage of detecting authentic hydroperoxides selectively. These methods are referred to as “FOX methods 1 and 2” (ferrous oxidation in xylenol orange). Method FOX1 is extremely sensitive [ɛ 560 (H 2 O 2 ) = 2.2 × 10 5 M -1 cm -1 ] and is readily applied to the measurement of low levels of water-soluble hydroperoxides present in aqueous phase; FOX2 [ɛ 560 (ROOH) = 4.5 × 10 4 M -1 cm -1 ] is used to determine levels of hydroperoxides present in the lipid phase, such as in lipoproteins, membranes, and fats.
Article
The present study investigated the chemopreventive potential of geraniol, an acyclic monoterpene alcohol, by monitoring the tumor incidence and analyzing the status of phase II detoxification agents, lipid peroxidation by products and antioxidants in 7,12-dimethylbenz(a)anthracene (DMBA) induced mouse skin carcinogenesis. Skin tumor was developed by painting DMBA (25 microg in 0.1 ml acetone mouse(-1)) in the shaved back of the mice, twice weekly for 8 weeks. We noticed 100% skin tumor formation in mice treated with DMBA alone. The status of phase II detoxification agents and antioxidants were decreased where as lipid peroxidation by products were increased in tumor bearing mice. Oral administration of geraniol at a dose of 250 mg kg(-1) body weight significantly prevented the tumor formation as well as brought back the status of phase II detoxification agents, lipid peroxidation by products and antioxidants to near normal range in DMBAtreated mice. Present results suggest that geraniol might have inhibited abnormal cell proliferation occurring in skin carcinogenesis by modulating the activities of phase II detoxification agents and through its free radical scavenging potential.
Article
Bioactive food components (BFACs) represent promising candidates for liver cancer chemoprevention. Among them, isoprenic derivatives (carotenoids, retinoids, perillyl alcohol, limonene, geraniol, farnesol, geranylgeraniol and β-ionone) can be highlighted. The relevance of animal models for the investigation of chemopreventive agents is supported by comparative functional genomic studies that reinforce the similarities between rodent and human hepatocarcinogenesis. Thus, characterization of BFACs in animal models as blocking and/or suppressing agents allows the establishment of the theoretical basis for the development of chemoprevention strategies. Dietary isoprenic derivatives actions on hepatocarcinogenesis may involve a block in carcinogen activation, induction of phase 2 enzymes and an antioxidant activity, as well as interference with cellular processes including cell communication, proliferation, apoptosis, differentiation and remodeling of preneoplastic lesions. Dietary isoprenic derivatives modulate molecular targets including HMG-CoA-reductase, Rho, nuclear receptors, c-myc, connexin 43, NF-κB and Nrf2. Several networks related to these targets are altered in early phases of hepatocarcinogenesis. This emphasizes the importance of such agents for the chemoprevention of hepatocellular carcinoma. Combinations of isoprenic derivatives or of these substances with other BFACs classes should be further investigated. Also, toxicity and bioavailability and pharmacokinetic aspects of these derivatives represent relevant issues in their development as chemopreventive agents. One major current limitation of the adoption of dietary isoprenic derivatives for liver cancer chemoprevention is the challenge in overcoming the initial preclinical phase in agent development. Dietary isoprenic derivatives that present liver cancer chemopreventive properties should be further explored in clinical trials, begining with the phase 0 approach.
Article
Quantification of intra-epidermal nerve fibers (iENFs) is an important approach to stage diabetic peripheral neuropathy (DPN) and is a promising clinical endpoint for identifying beneficial therapeutics. Mechanistically, diabetes decreases neuronal mitochondrial function and enhancing mitochondrial respiratory capacity may aid neuronal recovery from glucotoxic insults. We have proposed that modulating the activity and expression of heat shock proteins (Hsp) may be of benefit in treating DPN. KU-32 is a C-terminal Hsp90 inhibitor that improved thermal hypoalgesia in diabetic C57Bl/6 mice but it was not determined if this was associated with an increase in iENF density and mitochondrial function. After 16 weeks of diabetes, Swiss Webster mice showed decreased electrophysiological and psychosensory responses and a >30% loss of iENFs. Treatment of the mice with ten weekly doses of 20mg/kg KU-32 significantly reversed pre-existing deficits in nerve conduction velocity and responses to mechanical and thermal stimuli. KU-32 therapy significantly reversed the pre-existing loss of iENFs despite the identification of a sub-group of drug-treated diabetic mice that showed improved thermal sensitivity but no increase in iENF density. To determine if the improved clinical indices correlated with enhanced mitochondrial activity, sensory neurons were isolated and mitochondrial bioenergetics assessed ex vivo using extracellular flux technology. Diabetes decreased maximal respiratory capacity in sensory neurons and this deficit was improved following KU-32 treatment. In conclusion, KU-32 improved physiological and morphologic markers of degenerative neuropathy and drug efficacy may be related to enhanced mitochondrial bioenergetics in sensory neurons.
Article
A photometric method for determining acetylcholinesterase activity of tissue extracts, homogenates, cell suspensions, etc., has been described. The enzyme activity is measured by following the increase of yellow color produced from thiocholine when it reacts with dithiobisnitrobenzoate ion. It is based on coupling of these reactions: The latter reaction is rapid and the assay is sensitive (i.e. a 10 μ1 sample of blood is adequate). The use of a recorder has been most helpful, but is not essential. The method has been used to study the enzyme in human erythrocytes and homogenates of rat brain, kidney, lungs, liver and muscle tissue. Kinetic constants determined by this system for erythrocyte eholinesterase are presented. The data obtained with acetylthiocholine as substrate are similar to those with acetylcholine.
Article
Exploration of antioxidants of plant origin and scientific validation of their efficacies has unraveled bioactives from natural sources. In this study, two terpenoids camphene and geraniol were assessed for their cytoprotective and antioxidant potential using t-BHP stressed rat alveolar macrophages. Effect of these test substances along with a known plant derived antioxidant quercetin was seen on cell viability, some oxidative stress markers as well as on mitochondrial membrane potential. Both the test substances geraniol and camphene increased the cell viability significantly as indicated by MTT assay and LDH release assay, during pre-treatment of test compound. Camphene and geraniol showed 29% (P < 0.05) and 45% (P < 0.05) increase in SOD activity, 28% and 120% (P < 0.001) increase in GSH content and restored the mitochondrial membrane potential during pre-treatment as compared to stressed cells. Camphene and geraniol were found to significantly decrease lipid peroxidation, inhibit NO release (83.84% and 64.61%) and ROS generation in the pre-treated cells as compared to stressed cells. The test compounds also showed significant protection against ROS during post-treatment of the test compounds. Results indicate the pharmacological potential of these phytochemicals in lung inflammatory diseases where oxidative stress is a critical control point.
Article
Inflammation is an emerging patho-mechanism of diabetes and its complications. NF-κB pathway is one of the central machinery initiating and propagating inflammatory responses. The present study envisaged the involvement of NF-κB inflammatory cascade in the pathophysiology of diabetic neuropathy using BAY 11-7082, an IκB phosphorylation inhibitor. Streptozotocin was used to induce diabetes in Sprauge Dawley rats. BAY 11-7082 (1 & 3 mg/kg) was administered to diabetic rats for 14 days starting from the end of six weeks post diabetic induction. Diabetic rats developed deficits in nerve functions and altered nociceptive parameters and also showed elevated expression of NF-κB (p65), IκB and p-IκB along with increased levels of IL-6 & TNF-α and inducible enzymes (COX-2 and iNOS). Furthermore, there was an increase in oxidative stress and decrease in Nrf2/HO-1 expression. We observed that BAY 11-7082 alleviated abnormal sensory responses and deficits in nerve functions. BAY 11-7082 also ameliorated the increase in expression of NF-κB, IκB and p-IκB. BAY 11-7082 curbed down the levels of IL-6, TNF-α, COX-2 and iNOS in the sciatic nerve. Lowering of lipid peroxidation and improvement in GSH levels was also seen along with increased expression of Nrf2/HO-1. Thus it can be concluded that NF-κB expression and downstream expression of proinflammatory mediators are prominent features of nerve damage leading to inflammation and oxidative stress and BAY 11-7082 was able to ameliorate experimental diabetic neuropathy by modulating neuroinflammation and improving antioxidant defence.
Article
Neuropathy is a frequent complication in diabetes and most commonly seen as distal symmetrical sensorimotor polyneuropathy (PN). Involvement of the motor system is infrequently seen at the clinical examination. However, with the application of quantitative techniques, that is, isokinetic dynamometry, type 1 and type 2 diabetic patients have been detected to have weakness at the ankle and the knee. Muscle weakness is found only in diabetic patients with PN, while non-neuropathic patients even with long-term diabetes have normal strength. The weakness is closely related to signs and severity of PN. With the use of magnetic resonance imaging, muscle weakness is found to be paralleled by muscular atrophy, which is observed in the feet and at the lower leg. Following diabetic patients for 8-10 years, we have observed accelerated loss of muscle strength in patients with symptomatic PN; similarly, accelerated loss of muscle mass is observed in the feet and lower legs. In large-scale studies of diabetic and non-diabetic subjects, lower muscle quality in diabetic patients is also found. Thus, in addition to PN, diabetes per se leads to lower strength per unit striated muscle. Muscle weakness is related to the slowing of movements, unstable gait, and more frequent falls. Furthermore, motor dysfunction leads to an increased risk of developing a foot ulcer due to due to alterations of the biomechanics of the feet caused by muscle atrophy. This may lead to an increased skin pressure that may lead to foot ulceration and ultimately amputation. Muscle and balance training may improve strength, postural stability, and walking performance; however, this needs to be studied in more detail.
Article
Diabetes mellitus targets the peripheral nervous system in unique but disabling ways. Although several mechanisms may target peripheral neurons, they render a degenerative pattern of damage that begins in distal terminals. Moreover, sensory neurons are involved early, motor neurons later. By studying a variety of diabetic neuropathy models in rats, mice, and other species, an overall appreciation of its neurodegeneration emerges. Understanding how mechanisms of diabetes complications target peripheral neurons selectively may offer opportunities to intervene before irretrievable neuron loss develops.
Article
A toxicologic and dermatologic review of geraniol when used as a fragrance ingredient is presented.
Article
We evaluated the effects of rose oil on the peroxisome proliferator-activated receptor (PPAR) and cyclooxygenase-2 (COX-2). Citronellol and geraniol, the major components of rose oil, activated PPARα and γ, and suppressed LPS-induced COX-2 expression in cell culture assays, although the PPARγ-dependent suppression of COX-2 promoter activity was evident only with citronellol, indicating that citronellol and geraniol were the active components of rose oil.
Article
Long-standing diabetes and complications thereof particularly, neuropathy stands for one of the major causes of morbidity across the globe. It is postulated that excessive production of reactive oxygen species is a key component in the development and progression of diabetic neuropathy. Oxidative damage is the most common concluding pathway for various pathogenetic mechanisms of neuronal injury in diabetic neuropathy. However despite optimistic preclinical data, it is still very ambiguous that why antioxidants have failed to demonstrate significant neuroprotection in humans. A growing body of evidences now suggests that strategies utilizing a more targeted approach like focusing on Nrf2 (a transcription factor modulating oxidative stress) may provide an enthralling avenue to optimize neuroprotection in diabetes and diabetic neuropathy. This review presents an emerging concept of Nrf2 in diabetic neuropathy; thus looking forward to newer strategies for combating the oxidant induced damage.
Article
The neuropathic pain syndrome is complex. Current drugs to treat neuropathic pain, including anticonvulsivants and antidepressants, fail in up to 40-50% of the patients, while in the rest of them total alleviation is not normally achieved. Increased research advances in the neurobiology of neuropathic pain have not translated in more successful pharmacological treatments by the moment, but recent progress in the experimental methods available for this purpose could result in significant advances in the short term. One rational possibility for the pharmaceutical development of new drugs, including target identification, drug design and evaluation studies, could be to focus on mimicking what organism does to limit nerve damage or to enhance the regeneration of injured axons. Following this strategy, neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been postulated as potential pharmacological targets to treat neuropathic pain. In addition, during the last few years, strong scientific evidences point to novel neurotrophic factors, such as pleiotrophin (PTN), as important factors to limit neuropathic pain development because of their remodeling and angiogenic actions in the injured area. This review focuses on recent research advances identifying new pharmacological targets in the treatment of the cause, not only the symptoms, of neuropathic pain.
Article
The aim of the present study was to investigate the effect of ginger on oxidative stress markers in the mitochondrial fractions of cerebral cortex (CC), cerebellum (CB), hippocampus (HC) and hypothalamus (HT) of diabetic rats. Diabetes exacerbates neuronal injury induced by hyperglycemia mediated oxidative damage. A marked decrease in anti-oxidant marker enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), reduced glutathione (GSH) and increase in malondialdehyde (MDA) was observed in the diabetic rats. Decreased activities of anti-oxidant enzymes in diabetic rats were augmented on oral administration of ginger. Moreover, ginger administration depleted the MDA level, which was earlier increased in the diabetic rats. These results suggest that ginger exhibit a neuroprotective effect by accelerating brain anti-oxidant defense mechanisms and down regulating the MDA levels to the normal levels in the diabetic rats. Thus, ginger may be used as therapeutic agent in preventing complications in diabetic patients.
Article
The Na+ and Ca(2+)-permeable melastatin related transient receptor potential 2 (TRPM2) channels can be gated either by ADP-ribose (ADPR) in concert with Ca(2+) or by hydrogen peroxide (H(2)O(2)), an experimental model for oxidative stress, binding to the channel's enzymatic Nudix domain. Since the mechanisms that lead to TRPM2 gating in response to ADPR and H(2)O(2) are not understood in neuronal cells, I summarized previous findings and important recent advances in the understanding of Ca(2+) influx via TRPM2 channels in different neuronal cell types and disease processes. Considering that TRPM2 is activated by oxidative stress, mediated cell death and inflammation, and is highly expressed in brain, the channel has been investigated in the context of central nervous system. TRPM2 plays a role in H(2)O(2) and amyloid β-peptide induced striatal cell death. Genetic variants of the TRPM2 gene confer a risk of developing Western Pacific amyotropic lateral sclerosis and parkinsonism-dementia complex and bipolar disorders. TRPM2 also contributes to traumatic brain injury processes such as oxidative stress, inflammation and neuronal death. There are a limited number of TRPM2 channel blockers and they seem to be cell specific. For example, ADPR-induced Ca(2+) influx in rat hippocampal cells was not blocked by N-(p-amylcinnomoyl)anthralic acid (ACA), the IP(3) receptor inhibitor 2-aminoethoxydiphenyl borate or PLC inhibitor flufenamic acid (FFA). However, the Ca(2+) entry in rat primary striatal cells was blocked by ACA and FFA. In conclusion TRPM2 channels in neuronal cells can be gated by either ADPR or H(2)O(2). It seems to that the exact relationship between TRPM2 channels activation and neuronal cell death still remains to be determined.
Article
Alzheimer disease (AD) is a neurodegenerative disorder in which oxidative stress is a key hallmark. It occurs early in disease pathogenesis and can exacerbate its progression. Several causes of oxidative stress have been determined over the years. First, mitochondria play an important role in the generation and accumulation of free radicals. In addition to mitochondria, inflammation can also induce oxidative damage, especially via microglia, and microglia are also important for Aβ clearance. In AD, both mitochondrial function and inflammatory response are affected, leading to increased ROS formation and oxidative damage to lipid, proteins, and nucleic acids. Some other sources have also been identified. From these findings, various neuroprotective strategies against ROS-mediated damages have been elaborated in AD research. This review recapitulates some of the major strategies used to prevent oxidative stress and disease progression. Outcomes from in vitro and in vivo studies using models of AD are encouraging. However, only a few clinical trials have provided positive results in terms of slowing down cognitive decline. Nonetheless, there is still hope for improved compounds that would better target pathways implicated in ROS production. In fact, facilitating the endogenous antioxidant system by modulating transcription has great promise for AD therapy.
Article
Diabetic encephalopathy, characterized by cognitive deficits involves hyperglycemia-induced oxidative stress. Impaired mitochondrial functions might play an important role in accelerated oxidative damage observed in diabetic brain. The aim of the present study was to examine the role of mitochondrial oxidative stress and dysfunctions in the development of diabetic encephalopathy along with the neuroprotective potential of N-acetylcysteine (NAC). Chronic hyperglycemia accentuated mitochondrial oxidative stress in terms of increased ROS production and lipid peroxidation. Significant decrease in Mn-SOD activity along with protein and non-protein thiols was observed in the mitochondria from diabetic brain. The activities of mitochondrial enzymes; NADH dehydrogenase, succinate dehydrogenase and cytochrome oxidase were decreased in the diabetic brain. Increased mitochondrial oxidative stress and dysfunctions were associated with increased cytochrome c and active caspase-3 levels in cytosol. Electron microscopy revealed mitochondrial swelling and chromatin condensation in neurons of diabetic animals. NAC administration, on the other hand was found to significantly improve diabetes-induced biochemical and morphological changes, bringing them closer to the controls. The results from the study provide evidence for the role of mitochondrial oxidative stress and dysfunctions in the development of diabetic encephalopathy and point towards the clinical potential of NAC as an adjuvant therapy to conventional anti-hyperglycemic regimens for the prevention and/or delaying the progression of CNS complications.
Article
The present study examined the role of dopamine and D(1)-and D(2)-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked anti-hypersensitivity in a rat model of neuropathic pain, as well as the possible underlying mechanisms. Results showed that microinjection of apomorphine [(R(-)-apomorphine hydrochloride)], a non-selective dopamine receptor agonist, into the VLO attenuated spared nerve injury (SNI)-induced mechanical allodynia in a dose-dependent manner. This effect was completely blocked by the D(2)-like dopamine receptor antagonist S(-)-raclopride(+)-tartrate salt (1.5 microg), but was enhanced by the D(1)-like dopamine receptor antagonist SCH23390 (R(+)-SCH-23390 hydrochloride, 5.0 microg). The attenuating effect of apomorphine on mechanical allodynia was mimicked by application of the D(2)-like dopamine receptor agonist quinpirole [((-)-quinpirole hydrochloride, 0.5, 1.0, and 2.0 microg)]. In addition, microinjection of larger doses (10 and 20 microg) of SCH23390 into the VLO significantly attenuated allodynia. Furthermore, microinjections of GABA(A) receptor antagonists, bicuculline [(+)-bicuculline,(S), 9(R)] and picrotoxin (200 and 300 ng for both drugs), into the VLO attenuated mechanical allodynia. A small dose of bicuculline or picrotoxin (100 ng) resulted in increased quinpirole (0.5 microg)-induced anti-allodynia. In contrast, GABA(A) receptor agonists, muscimol hydrochloride (250 ng) or THIP [(2,5,6,7-retrahydroisoxazolo(5,4-c)pyridine-3-ol hydrochloride, 1.0 microg)], blocked quinpirole (2.0 microg)-induced attenuation. These results suggest that the dopaminergic system is involved in mediating VLO-induced anti-hypersensitivity, activation of D(2)-like dopamine receptors, and inhibition of D(1)-like receptors resulting in anti-hypersensitivity. In addition, the mechanisms of GABAergic disinhibition might be involved in D(2)-like receptor mediating effects in neuropathic pain.
Article
Mitochondrial-mediated oxidative stress in response to high glucose is proposed as a primary cause of dorsal root ganglia (DRG) neuron injury in the pathogenesis of diabetic neuropathy. In the present study, we report a greater number of mitochondria in both myelinated and unmyelinated dorsal root axons in a well-established model of murine diabetic neuropathy. No similar changes were seen in younger diabetic animals without neuropathy or in the ventral motor roots of any diabetic animals. These findings led us to examine mitochondrial biogenesis and fission in response to hyperglycemia in the neurites of cultured DRG neurons. We demonstrate overall mitochondrial biogenesis via increases in mitochondrial transcription factors and increases in mitochondrial DNA in both DRG neurons and axons. However, this process occurs over a longer time period than a rapidly observed increase in the number of mitochondria in DRG neurites that appears to result, at least in part, from mitochondrial fission. We conclude that during acute hyperglycemia, mitochondrial fission is a prominent response, and excessive mitochondrial fission may result in dysregulation of energy production, activation of caspase 3, and subsequent DRG neuron injury. During more prolonged hyperglycemia, there is evidence of compensatory mitochondrial biogenesis in axons. Our data suggest that an imbalance between mitochondrial biogenesis and fission may play a role in the pathogenesis of diabetic neuropathy.
Article
Chemopreventive activities of the dietary isoprenoids β-ionone (βI) and geraniol (GOH) were evaluated during the promotion phase of hepatocarcinogenesis. Over 5 consecutive weeks, rats received daily 16 mg/100 g body weight (b.w.) of βI (βI group), 25 mg/100 g b.w. of GOH (GOH group), or only corn oil (CO group, controls). Compared to the CO group, the following was observed: only the βI group showed a decrease in the mean number of visible hepatocyte nodules (P<.05); βI and GOH groups had reduced mean number of persistent preneoplastic lesions (pPNLs) (P<.05), but no differences regarding number of remodeling PNL (rPNLs) were observed; only the βI group exhibited smaller rPNL size and percentage of liver sections occupied by pPNLs (P<.05), whereas the GOH group displayed a smaller percentage of liver sections occupied by rPNLs (P<.05); a trend was observed in the βI group, which showed reduced cell proliferation of pPNLs (P<.10), and the GOH group had increased apoptosis in pPNLs and rPNLs (P<.05); only the βI group displayed reduced total plasma cholesterol concentrations (P<.05) and increased hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase mRNA levels (P<.05); only the GOH group had lower hepatic membrane RhoA protein levels (P<.05); both the βI- and GOH-treated groups had higher hepatic concentrations of βI and GOH, respectively (P<.05). Given these data, βI and GOH show promising chemopreventive effects during promotion of hepatocarcinogenesis by acting through distinct mechanism of actions: βI may inhibit cell proliferation and modulate HMGCoA reductase, and GOH can induce apoptosis and inhibit RhoA activation.
Article
The study was to find out the effect of Vitamin D3 supplementation on preventing the altered gene expression of cholinergic, dopaminergic, insulin receptors and GLUT3 gene expression in cerebellum of diabetic rats. Radioreceptor binding assays and gene expression were done in the cerebellum of male Wistar rats. Rota rod has been used to evaluate motor coordination. Our results showed a significantly increased gene expression of dopamine D2, muscarinic M1, M3, alpha7 nicotinic acetylcholine, insulin receptors, acetylcholine esterase, GLUT3 and Vitamin D receptor in the cerebellum of diabetic rats. There was a down-regulation of dopamine D1 receptor. Total dopamine receptor showed a decreased and total muscarinic, muscarinic M1 and M3 receptors showed an increased binding parameter, B(max). Rota rod experiment showed a significant decrease in the retention time on the rotating rod in diabetic while treatment improved retention time near to control. Vitamin D3 and insulin treatment markedly recovered the altered gene expression and binding parameters to near control. Our study showed Vitamin D3 functional regulation through dopaminergic, cholinergic and insulin receptors and glucose transport mechanism through GLUT3 in the cerebellum of diabetic rats which play a major role in neuroprotection in diabetes which has clinical application.
Article
The objective of the present study was to investigate the effect of the administration of resveratrol (RV) on memory and on acetylcholinesterase (AChE) activity in the cerebral cortex, hippocampus, striatum, hypothalamus, cerebellum and blood in streptozotocin-induced diabetic rats. The animals were divided into six groups (n=6-13): Control/saline; Control/RV 10 mg/kg; Control/RV 20 mg/kg; Diabetic/saline; Diabetic/RV 10 mg/kg; Diabetic/RV 20 mg/kg. One day after 30 days of treatment with resveratrol the animals were submitted to behavioral tests and then submitted to euthanasia and the brain structures and blood were collected. The results showed a decrease in step-down latency in diabetic/saline group. Resveratrol (10 and 20 mg/kg) prevented the impairment of memory induced by diabetes. In the open field test, no significant differences were observed between the groups. In relation to AChE activity, a significant increase in diabetic/saline group (P<0.05) was observed in all brain structures compared to control/saline group. However, AChE activity decreased significantly in control/RV10 and control/RV20 (P<0.05) groups in cerebral cortex, hippocampus and striatum, while no significant differences were observed in diabetic/RV10 and diabetic/RV20 groups in all brain structures compared to control/saline group. Blood AChE activity increased significantly in diabetic/saline group (P<0.05) decreased in control/RV10, control/RV20 and diabetic/RV20 groups (P<0.05) compared to control/saline group. In conclusion, the present findings showed that treatment with resveratrol prevents the increase in AChE activity and consequently memory impairment in diabetic rats, demonstrating that this compound can modulate cholinergic neurotransmission and consequently improve cognition.
Article
Diabetes-induced damage to peripheral nerve culminates in development of peripheral diabetic neuropathy (PDN), one of the most devastating complications of diabetes mellitus and a leading cause of foot amputation. The pathogenesis of PDN occurs as a consequence of complex interactions among multiple hyperglycemia-initiated mechanisms, impaired insulin signaling, inflammation, hypertension, and disturbances of fatty acid and lipid metabolism. This review describes experimental new findings in animal and cell culture models as well as clinical data suggesting the importance of 1) previously established hyperglycemia-initiated mechanisms such as increased aldose reductase activity, non-enzymatic glycation/glycooxidation, activation of protein kinase C, 2) oxidative-nitrosative stress and poly(ADP-ribose) polymerase activation; 3) mitogen-activated protein kinase and cyclooxygenase-2 activation, impaired Ca(++) homeostasis and signaling, and several other mechanisms, in PDN.
Article
The present study was aimed at investigating the ameliorative effect of Ocimum sanctum in sciatic nerve transection (axotomy)-induced peripheral neuropathy in rats. Sciatic nerve transection-induced axonal degeneration was assessed histopathologically. Paw pressure, Von Frey Hair, tail cold-hyperalgesia, motor in-coordination tests were performed to assess the extent of neuropathy. Biochemical estimations of thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH), and total calcium levels were also performed. Methanolic extract of Ocimum sanctum at different doses (50, 100 and 200mg/kg p.o.) was administered for 10 consecutive days starting from the day of surgery. Administration of Ocimum sanctum attenuated sciatic nerve transection-induced axonal degeneration, reduction of nociceptive threshold and motor in-coordination. Moreover, it also attenuated axotomy-induced rise in TBARS, total calcium and decrease in GSH levels in a dose-dependent manner. Anti-oxidant and calcium attenuating actions may be responsible for observed ameliorative effects of Ocimum sanctum in axotomy-induced neuropathy.
Article
The reaction of lipid peroxides in animal tissues with thiobarbituric acid was dependent on pH of the reaction mixture as was the case for linoleic acid hydroperoxide. The optimum pH was found to be 3.5. Taking this fact into consideration, a standard procedure for the assay of lipid peroxide level in animal tissues by their reaction with thiobarbituric acid was developed as follows. Ten percent ( tissue homogenate was mixed with sodium dodecyl sulfate, acetate buffer (pH 3.5), and aqueous solution of thiobarbituric acid. After heating at 95°C for 60 min, the red pigment produced was extracted with n-butanol-pyridine mixture and estimated by the absorbance at 532nm. As an external standard, tetramethoxy-propane was used, and lipid peroxide level was expressed in terms of nmol malondialdehyde. Using this method, the liped peroxide level in the liver of rats suffering from carbon tetrachloride intoxication was investigated. The results were in good agreement with previously reported data obtained by measuring diene content.