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Oxidative stress induced neurotoxicity is increasingly perceived as an important neuropathologic mechanism underlying the motor and behavioral phenotypes associated with Huntington's disease (HD). Repeated exposure to 3-nitropropionic acid (3-NP) induces neurotoxic changes which closely simulate the neuropathological and behavioral characteristics of HD. This study aimed at evaluating the prophylactic effects of the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) inhibitor "harmine" against 3-NP-indued neurotoxicity and HD-like symptoms. The potential prophylactic effect of harmine (10 mg/kg/day; intraperitoneal) was investigated on 3-NP-induced motor and cognitive HD-like deficits, nuclear factor erythroid 2 like 2 (NRF2), AMP kinase (AMPK) and p21 protein levels and the gene expression of haem oxygenase-1 (Ho-1), NAD(P)H: quinone oxidoreductase-1 (Nqo-1) and p62 in addition to redox imbalance and histological neurotoxic changes in the striatum, prefrontal cortex, and hippocampus of male Wistar rats. Harmine successfully increased the protein levels of NRF2, AMPK and p21 and the gene expression of Ho-1 , Nqo-1 and p62 , restored redox homeostasis, and reduced CASPASE-3 level. This was reflected in attenuation of 3-NP-induced neurodegenerative changes and improvement of rats' motor and cognitive performance. This study draws attention to the protective role of harmine against 3-NP-induced motor and cognitive dysfunction that could be mediated via enhancing NRF2-mediated signaling with subsequent amelioration of oxidative stress injury via NRF2 activators, p21 and AMPK, in the striatum, prefrontal cortex, and hippocampus which could offer a promising therapeutic tool to slow the progression of HD. • The DYRK1A inhibitor "harmine" prevents 3-NP-induced neurotoxicity. • Harmine improves motor and cognitive performance in 3-NP-exposed rats. • Harmine prevents oxidative stress injury via enhancing NRF2-mediated signaling. • Harmine enhances the level of NRF2 activators, p21 and AMPK. • Targeting DYRK1A offers a promising therapeutic tool to slow the progression of HD. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by involuntary bizarre movements, psychiatric symptoms, dementia, and early death. Several studies suggested neuroprotective activities of inosine; however its role in HD is yet to be elucidated. The current study aimed to demonstrate the neuroprotective effect of inosine in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats while investigating possible underlying mechanisms. Rats were randomly divided into five groups; group 1 received i.p. injections of 1% DMSO, whereas groups 2, 3, 4, and 5 received 3-NP (10 mg/kg, i.p.) for 14 days, concomitantly with inosine (200 mg/kg., i.p.) in groups 3, 4, and 5, SCH58261, a selective adenosine 2A receptor (A2AR) antagonist, (0.05 mg/kg, i.p.) in group 4, and PD98059, an extracellular signal-regulated kinase (ERK) inhibitor, (0.3 mg/kg, i.p.) in group 5. Treatment with inosine mitigated 3-NP-induced motor abnormalities and body weight loss. Moreover, inosine boosted the striatal brain-derived neurotrophic factor (BDNF) level, p-tropomyosin receptor kinase B (TrKB), p-ERK, and p-cAMP response element-binding protein (CREB) expression, which subsequently suppressed oxidative stress biomarkers (malondialdehyde and nitric oxide) and pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin-1β) and replenished the glutathione content. Similarly, histopathological analyses revealed decreased striatal injury score, the expression of the glial fibrillary acidic protein, and neuronal loss after inosine treatment. These effects were attenuated by the pre-administration of SCH58261 or PD98059. In conclusion, inosine attenuated 3-NP-induced HD-like symptoms in rats, at least in part, via the activation of the A2AR/BDNF/TrKB/ERK/CREB signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Kaempferol is a natural antioxidant present in vegetables and fruits used in human nutrition. In previous work, we showed that intraperitoneal (i.p.) kaempferol administration strongly protects against striatum neurodegeneration induced by i.p. injections of 3-nitropropionic acid (NPA), an animal model of Huntington's disease. Recently, we have shown that reactive A1 astrocytes generation is an early event in the neurodegeneration induced by NPA i.p. injections. In the present work, we have experimentally evaluated the hypothesis that kaempferol protects both against the activation of complement C3 protein and the generation of reactive A1 astrocytes in rat brain striatum and hippocampus. To this end, we have administered NPA and kaempferol i.p. injections to adult Wistar rats following the protocol described in previous work. Kaempferol administration prevents proteolytic activation of complement C3 protein and generation of reactive A1 astrocytes NPA-induced in the striatum and hippocampus. Also, it blocked the NPA-induced increase of NF-κB expression and enhanced secretion of cytokines IL-1α, TNFα, and C1q, which have been linked to the generation of reactive A1 astrocytes. In addition, kaempferol administration prevented the enhanced production of amyloid β peptides in the striatum and hippocampus, a novel finding in NPA-induced brain degeneration found in this work. • Kaempferol prevents the NPA-induced complement C3 protein activation in rat brain. • Kaempferol protects against reactive A1 astrocytes induction by NPA in rat brain. • Kaempferol blocks the NPA-induced increase of IL-1α, TNFα and C1q in rat brain. • Kaempferol prevents the NPA-induced NF-κB expression in striatum and hippocampus. • Kaempferol blocks NPA-induced amyloid β peptides production in striatum and hippocampus. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an inherited devastating neurodegenerative disorder with disabling motor and cognitive derangements that hinder the patients from performing their daily activities. The present study was carried out to investigate telmisartan-induced neuroprotection against 3-nitropropionic acid (3-NP) model of HD in rats. Telmisartan was administered orally with a dose of 10 mg/kg/day, 1 h prior to 3-NP (10 mg/kg/day, i.p) for 14 days. 3-NP-injected animals which were treated with telmisartan showed marked improvement in muscle strength and motor functions evaluated by rotarod, grip strength, and open field tests. Moreover, administration of telmisartan attenuated 3-NP-induced oxidative stress, neuro-inflammation, and apoptosis with prominent decline in malondialdehyde striatal content in addition to NADPH oxidase reduced expression contrary to noticeable increment in reduced glutathione content. Additionally, the pro-inflammatory markers; tumor necrosis factor-α, interleukin-1β, prostaglandin E2, and cyclooxygenase-2 contents were significantly reduced along with decreased active caspase-3 immunoreactivity. Telmisartan was also implicated in the modulation of phosphatidyl inositol 3-kinase/protein kinase B/glycogen synthase kinase-3β (PI3K/Akt/GSK-3β) and extracellular signal-regulated kinase (ERK) 1/2 cascades with consequent anti-oxidative, anti-inflammatory, and anti-apoptotic effects. Photomicrographs of telmisartan-treated animals confirmed its neuroprotective effects showing dismounted neuronal death and obvious increase in neuronal survival. These beneficial effects could be attributed to telmisartan's ability to induce peroxisome proliferator activated receptor-γ expression as well as its well-known blocking effect of angiotensin-II receptors type 1. Subsequently, telmisartan is deemed as a promising candidate for HD management. [Display omitted] • Telmisartan mitigated 3-NP-induced oxidative stress, neuro-inflammation, and apoptosis. • Telmisartan improved rats' motor functions as well as the striatal photomicrographs. • PPAR-γ agonistic activity and AT1R blockade are proposed as the major provocative of telmisartan –induced neuroprotection. • Telmisartan could modulate PI3K/Akt/GSK-3β pathway which plays a fundamental role in Huntington's disease pathogenesis. • Telmisartan is a prosperous candidate in the management of Huntington's disease. [ABSTRACT FROM AUTHOR]

Despite the fact that heterotrophic nitrification was identified more than 100 years ago, the biochemistry of heterotrophic nitrifiers is poorly known and their contribution to nitrification in soil is still speculative. Heterotrophic nitrifiers need organic compounds as their energy source in contrast to the chemolithotrophic nitrifiers. Most of the potential pathways for nitrite/nitrate production by heterotrophs can be considered as secondary metabolism. Only nitrification and simultaneous denitrification by some heterotrophic bacteria is known to have connection to the energy metabolism. Evidently, the nitrification pathways of bacteria and fungi differ. Some heterotrophic bacteria oxidizing ammonia have ammonia monooxygenase (AMO), but there are also heterotrophic bacteria oxidizing ammonia without AMO. The structure of AMO of chemolithotrophic ammonia oxidizers and heterotrophs differs. AMO has not been found in nitrifying fungi. The conditions for heterotrophic nitrification in soil highly differ from those in waste waters where heterotrophic nitrification activity can be high. Heterotrophic nitrification in soil is limited by the low availability of easily decomposable organic substrates. Possible nitrification by heterotrophs in the rhizosphere and endophytic root microbes gaining a good supply of substrates from plants is not known. Fungi are of special interest in heterotrophic nitrification in soil because fungi can evidently nitrify not only easily decomposable substrates but also when decomposing recalcitrant organic compounds (like lignin) which are abundant in soil. Nitrite/nitrate production from easily decomposable nitrogenous organic compounds, such as amino acids, is common among heterotrophic bacteria and fungi. The general conclusion that heterotrophs use solely an "organic pathway" in their nitrification is, however, not valid because also ammonia can be oxidized. Owing to the diverse, poorly known biochemistry of heterotrophic nitrification and methodological difficulties to differentiate heterotrophic and chemolithotrophic nitrification in soil, the role of heterotrophic nitrification in soil nitrogen cycle remains uncertain. • Heterotrophic nitrification involves several poorly known mechanisms. • Heterotrophic bacteria, unlike fungi can possess ammonia monooxygenase. • Fungi are able to nitrify easily decomposable and recalcitrant organic compounds. • The methods available do not allow accurate determination of nitrification in soil. [ABSTRACT FROM AUTHOR]

[Display omitted] • The structures, bioactivities and mechanisms of phytoconstituents for the management of Huntington's disease were mentioned. • Clinical trials conducted on some phytoconstituents and vitamins against Huntington's disease were included. • Other medicinal properties of phytoconstituents in concern were mentioned in the form of figure. • Pathophysiological mechanisms implicated in Huntington's disease were elaborated. Among several neurodegenerative diseases, Huntington disease has posed a major threat across the world, particularly in the aged population. The disease is caused due to expansion of cytosine-adenine-guanine repeats which further triggers the formation of a mutant huntingtin protein responsible for neuronal death. Numerous pathophysiologic mechanisms have been implicated in Huntington's disease. Striatum and cortex represent the most affected parts of the brain. Even though a wide range of medicines are available but they possess serious side effects. Therefore, the emergence of nutraceuticals derived from natural sources has received great attention in the pharmaceutical domain. Nutraceuticals are health-promoting supplements and enhance immunity in human beings. Currently, oxidative stress is the leading factor for chronic diseases that occur due to low intake of antioxidants. Herbal nutraceuticals are said to be enriched with a massive number of antioxidants. Therefore, this article throws light on various herbal nutraceuticals and their noteworthy effects on Huntington's disease. [ABSTRACT FROM AUTHOR]

Aim Huntington's disease ( HD) is an autosomal dominant disorder, for which clinically available drugs offer only symptomatic relief. These prescription drugs are not free of side effects, and the patients usually suffer from anxiety and depression. We investigated quercetin, a dietary flavonoid with free radical scavenging properties, for its beneficial potential if any, in 3-nitropropionic acid (3- NP)-induced HD in rats where both drugs were administered simultaneously. Methods Performance of rats on beam balancing, elevated plus maze and gait traits were investigated following 3- NP and/or quercetin treatments for 4 days. Striatal biogenic amine levels and monoamine oxidase activity were assayed. Striatal sections were examined for Cd11B and glial fibrillary acidic protein immunoreactivity, and for evidences of neuronal lesion. Results Quercetin significantly attenuated 3- NP-induced anxiety, motor coordination deficits, and gait despair. While the dopaminergic hyper-metabolism was unaffected, quercetin provided a significant reduction of 3- NP mediated increase in serotonin metabolism. Quercetin failed to affect 3- NP-induced striatal neuronal lesion, but decreased microglial proliferation, and increased astrocyte numbers in the lesion core. Conclusion These results taken together suggest that quercetin could be of potential use not only for correcting movement disturbances and anxiety in HD, but also for addressing inflammatory damages. [ABSTRACT FROM AUTHOR]

Highlights: [•] Systemic infusion of 3-NP increased ROS and led striatal cell loss. [•] ASK1 down-regulation decreased striatal cell death without scavenging ROS. [•] Adding ASK1protein to SOD tg aggravated striatal degeneration. [•] ASK1 activation induced by ROS is an important step of the 3-NP pathophysiology. [Copyright &y& Elsevier]

Huntington's disease (HD) is a genetic neurodegenerative disorder that is characterized by severe striatal atrophy with extensive neuronal loss and gliosis. Although the molecular mechanism is not well understood, experimental studies use the irreversible mitochondrial inhibitor 3-nitropropionic acid (3-NP) to mimic the neuropathological features of HD. In this study, the role of autophagy as a neuroprotective mechanism against 3-NP-induced astrocyte cytotoxicity was evaluated. Autophagy is a catabolic process that is essential for the turnover of cytosolic proteins and organelles and is involved in the modulation of cell death and survival. We showed that 3-NP-induced apoptosis, which was accompanied by Bax and Beclin-1 upregulation, was dependent on acidic vesicular organelle (AVO) formation after a continuous exposure to 3-NP for 12 h. The upregulation of Bax and Beclin-1 as well as AVO formation were normalized 24 h after 3-NP exposure. [ABSTRACT FROM AUTHOR]

Highlights: [•] We examined cochlea K+ recycling-related proteins after acute energy failure. [•] Connexin 26 increased and Na,K-ATPase and NKCC1 disappeared in the spiral ligament. [•] Kir4.1 and L-PGDS decreased in the stria vascularis. [•] NKCC1 and connexin 26 were present in the center of the limbus despite nuclei loss. [ • ] Fibrocyte changes may compensate damaged K+ recycling and preserve ATP. [ABSTRACT FROM AUTHOR]

3-Nitropropionate (3-NPA) is a nitro aliphatic compound found in numerous plants and fungi. The nitro compound exists in equilibrium with its conjugate base, propionate 3-nitronate (P3N) and has a p Ka approaching the physiological range of 9.1. Since 1920, more than 30 species of plant and fungi have been identified as producing 3-NPA as a means of defense from herbivores. Glycoside products containing moieties of 3-NPA found in parts of the plants most accessible to herbivores can be easily hydrolyzed to free 3-NPA by bacterial enzymes in the gut of animals. In addition to providing a defense mechanism, the nitro compound is an intermediate in the nitrification process of leguminous plants. The synthesis of 3-NPA in these plants and fungi is poorly understood. P3N, which readily forms from 3-NPA at physiological pH, is a potent inhibitor of the key enzyme succinate dehydrogenase in the Krebs cycle and electron transport chain. Inhibition of succinate dehydrogenase in humans and livestock causes neurotoxicity and in some cases death. Several enzymes catalyze the oxidation of 3-NPA or P3N; all contain a noncovalently bound flavin cofactor and are found in the organisms that produce 3-NPA. With kcat/ Km values of >106 M−1 s−1, nitronate monooxygenases can quickly and efficiently oxidize P3N to malonic semialdehyde as a means of protecting the organism from killing itself. Although it was discovered almost a century ago, the biochemistry and physiological role of 3-NPA/P3N are just emerging. © 2013 IUBMB Life, 65(9):759-768, 2013 [ABSTRACT FROM AUTHOR]

Abstract: Phosphodiesterase inhibitors have been reported to be beneficial in cognitive and motor disorders. In the present study, we have investigated the effects of RO 20-1724 (PDE4 inhibitor) and sildenafil (PDE5 inhibitor) in 3-nitropropionic acid (3-NP) induced experimental Huntington's disease in rats. 3-Nitropropionic acid was administered for 14 days (10mg/kg i.p.) 1h following 3-NP administration, the rats were treated with either vehicle, RO 20-1724 (0.25 and 0.5mg/kg i.p.) or sildenafil (2 and 4mg/kg i.p.) for 14 days. Cognitive functions were assessed by using Morris water maze whereas, motor functions were assessed by spontaneous locomotor activity, limb withdrawal and suspended wire test at different time points. Biochemically, markers of oxidative stress and cell damage, such as reduced glutathione, malondialdehyde, nitrite and lactate dehydrogenase levels were assessed terminally in the brain homogenate. Chronic administration of 3-NP produced significant decrease in body weight, showed marked abnormalities in cognitive and motor functions. Further, significant oxidative–nitrosative stress and cell damage was also observed. Chronic administration of RO 20-1724 and sildenafil in 3-NP treated rats significantly and dose dependently attenuated 3-NP induced behavioral and biochemical abnormalities in rats. Both these drugs were equally effective in attenuating 3-NP induced neurotoxicity. These results suggesting that the inhibition of PDE4 and PDE5 would be therapeutic in neurodegenerative disorders associated with cognitive and motor dysfunction. [Copyright &y& Elsevier]

Highlights: [•] Subtoxic concentrations caused mitochondrial dysfunction without affecting viability. [•] Each neurotoxicant led to concentration-dependent decreases in TMRM fluorescence. [•] The antioxidant, deferoxamine, protected against loss of TMRM fluorescence. [•] Exposure to 100μM of each toxicant led to similar patterns of protein carbonylation. [Copyright &y& Elsevier]

Hi, neighbor! The first organocatalyzed asymmetric transfer hydrogenation of aromatic nitro compounds was successfully developed with up to 99 % ee. The new methodology provides a direct and facile access to enantiopure cyclic nitro compounds with two contiguous stereocenters. [ABSTRACT FROM AUTHOR]

The compound 3-nitropropionic acid is a potent neurotoxic agent in animals and well-known as a potent inhibitor of Mycobacterium tuberculosis. In this research, we were able to extract this compound from the endophytic fungus, Phomopsis longicolla (FJ62759), isolated from Trichilia elegans A. JUSS ssp. elegans. The aim of this study was the isolation of secondary metabolites produced by P. longicolla, the chemical identification of these compounds and evaluation of their antimicrobial and insecticidal activity. To accomplish these goals, the fungus was cultured in BD broth for 25 days without agitation at 28 °C, and then the broth was separated from the mycelium. The supernatant was partitioned with dichloromethane (CHCl), ethyl acetate (EtOAc), and butanol (BuOH) solvents resulting in 3 extracts. However, only the EtOAc extract was used for fractionation and chemical identification because it had the greatest mass. After common chromatographic procedures, the fractions were analyzed by nuclear magnetic resonance to elucidate the chemical components. This procedure resulted in the identification of 3-nitropropionic acid in the D fraction. Evaluation of the insecticidal and antimicrobial activity of this compound has been accomplished, and the results indicate good inhibition of the citrus pathogen Guignardia citricarpa and cocoa pathogen Moniliophthora perniciosa and slight inhibition of the human bacterial pathogens Micrococcus luteus, Salmonella typhi and slight inhibition of phytopathogenic bacteria Xanthomonas axonopodis pv. phaseoli. The evaluation of insecticide activity did not show mortality of the Diatraea saccharalis larvae by the metabolite 3-nitropropionic acid in the D fraction. The results suggest that P. longicolla is a bioactive metabolic producing endophytic fungus with biotechnological properties. [ABSTRACT FROM AUTHOR]

Three ponies continuously grazed a pasture containing an estimated 24% Indigofera spicata (wet weight basis) for 4-6 weeks in April and May 2004. They developed ataxia, paresis, depression, muscle fasciculations, dysphagia, ptyalism and halitosis. Two also developed corneal opacity. One pony recovered with supportive treatment, but the other two were euthanased and necropsied. Neuropathology was not present in either case, but both livers had periacinar and periportal lymphocytic infiltrations and hydropic degeneration of mid-zonal hepatocytes, with mild to moderate periacinar necrosis also evident in one. The I. spicata contained 2.66 mg 3-nitropropionic acid (3- NPA)/g dry matter and 1.5 mg indospicine/g dry matter. Indospicine, but not 3- NPA, was detected in serum from both of the euthanased ponies and indospicine was detected in heart, liver and muscle from the one pony in which this assay was performed. The clinical syndrome closely resembled 'Birdsville horse disease' caused by I. linnaei and was similar to that reported in horses poisoned by the closely related species I. hendecaphylla and to 3- NPA poisoning of other animals, including humans. 3- NPA is thought to cause this neurological syndrome. To our knowledge, this is the first authenticated report of I. spicata poisoning in grazing animals. We also report here the first published evidence that 3- NPA and indospicine exist in naturalised I. spicata in Australia and of the formation of indospicine residues in tissues of animals grazing paddocks infested with I. spicata. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate the effects of bis selenide on Huntington disease (HD)-like signs induced by 3-nitropropionic acid (3-NP) in rats. To this aim, rats were treated for 4 days with bis selenide (5 or 20 mg/kg/day, per oral) 30 min before 3-NP (20 mg/kg/day, intraperitoneally). The body weight gain, locomotor activity, motor coordination, and biochemical parameters in striatal preparations were assessed 24 h after the last injection of 3-NP. The highest dose of bis selenide was effective in protecting against body weight loss and motor coordination deficit induced by 3-NP. The impairment of locomotor activity caused by 3-NP was abolished by bis selenide at both doses. Bis selenide (5 and 20 mg/kg) partially restored succinate dehydrogenase activity inhibited after 3-NP exposure. The dose of 20 mg/kg of bis selenide recovered partially δ-aminolevulinic acid dehydratase activity, and totally Na, K-ATPase activity, two sulfhydryl enzymes sensitive to oxidizing agents, which had their activities inhibited by 3-NP. Also, 3-NP led to an increase in protein carbonyl levels and glutathione reductase activity and inhibited catalase activity-alterations that were reversed by bis selenide administration at both doses. The highest dose of bis selenide was effective against the increase of RS levels, the depletion of reduced glutathione content, and the inhibition of glutathione peroxidase activity induced by 3-NP. Bis selenide was not effective against inhibition of SOD activity caused by 3-NP. These findings demonstrate that bis selenide elicited protective effects against HD-like signs induced by 3-NP in rats. [ABSTRACT FROM AUTHOR]

Abstract: This study evaluated and compared the potential protective effects of probucol and succinobucol, two lipid-lowering compounds with anti-inflammatory and antioxidant properties, on oxidative stress and mitochondrial dysfunction induced by 3-nitropropionic acid (3-NP, a succinate dehydrogenase (SDH) inhibitor largely used as model of Huntington''s disease) in rat brain mitochondria-enriched synaptosomes. 3-NP caused significant inhibition of mitochondrial complex II activity, induced mitochondrial dysfunction and oxidative stress. Probucol and succinobucol prevented oxidative stress, but only succinobucol was able to prevent the mitochondrial dysfunction induced by 3-NP. Succinobucol, which did not recover complex II inhibition, was able to protect against 3-NP-induced decreased of MTT reduction, indicating that SDH is not the only enzyme responsible for MTT reduction. The present findings suggest that succinobucol might be a novel strategy to slow or halt oxidative events in neurodegenerative conditions. [Copyright &y& Elsevier]

Abstract: The study was designed to investigate the beneficial effect of quercetin supplementation in 3-nitropropionic acid (3-NP) induced model of Huntington''s disease (HD). HD was induced in rats by administering sub-chronic dose of 3-NP, intraperitoneally, twice daily for 17days. Quercetin was supplemented at a dose of 25mg/kg body weight by oral gavage for 21days. At the end of treatment, mitochondrial bioenergetics, mitochondrial swelling, oxidative stress, neurobehavioral deficits and histopathological changes were analyzed. Quercetin supplementation was able to reverse 3-NP induced inhibition of respiratory chain complexes, restore ATP levels, attenuate mitochondrial oxidative stress in terms of lipid peroxidation and prevent mitochondrial swelling. Quercetin administration also restored the activities of superoxide dismutase and catalase along with thiol content in 3-NP treated animals. Beneficial effect of quercetin administration was observed on 3-NP induced motor deficits analyzed by narrow beam walk and footprint analysis. Histopathological analysis of 3-NP treated rats revealed pyknotic nuclei and astrogliosis in striatum, which were reduced or absent in quercetin supplemented animals. Altogether, our results show that quercetin supplementation to 3-NP induced HD animals ameliorated mitochondrial dysfunctions, oxidative stress and neurobehavioral deficits in rats showing potential of this flavonoid in maintaining mitochondrial functions, suggesting a putative role of quercetin in HD management. [Copyright &y& Elsevier]

Background and Aim: Huntington's disease (HD) is a rare inherited disease portrayed with marked cognitive and motor decline owing to extensive neurodegeneration. NADPH oxidase is considered as an important contributor to the oxidative injury in several neurodegenerative disorders including HD. Thus, the present study explored the possible neuroprotective effects of diapocynin, a specific NADPH oxidase inhibitor, against 3-nitropropionic acid (3-NP) model of HD in rats., Methods: Animals received diapocynin (10 mg/kg/day, p.o), 30 min before 3-NP (10 mg/kg/day, i.p) over a period of 14 days., Results: Diapocynin administration attenuated 3-NP-induced oxidative stress with significant increase in reduced glutathione, glutathione-S-transferase, nuclear factor erythroid 2-related factor 2, and brain-derived neurotrophic factor striatal contents contrary to NADPH oxidase (NOX2; gp91phox subunit) diminished expression. Moreover, diapocynin mitigated 3-NP-associated neuroinflammation and glial activation with prominent downregulation of nuclear factor-Кβ p65 and marked decrement of inducible nitric oxide synthase content in addition to decreased immunoreactivity of ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein; markers of microglial and astroglial activation, respectively. Treatment with diapocynin hindered 3-NP-induced apoptosis with prominent decrease in tumor suppressor protein and Bcl-2-associated X protein contents whereas the anti-apoptotic marker; B-cell lymphoma-2 content was noticeably increased. Diapocynin neuroprotective effects could be attributed to silent information regulator 1 upregulation which curbed 3-NP-associated hazards resulting in improved motor functions witnessed during open field, rotarod, and grip strength tests as well as attenuated 3-NP-associated histopathological derangements., Conclusion: The present findings indicated that diapocynin could serve as an auspicious nominee for HD management., (© 2022. The Author(s).)

Background: Naringenin is a powerful antioxidant and anti-inflammatory flavonoid which has been widely used as a therapeutic agent in various toxic models. However, few studies have clearly discussed the neuromodulatory effects of naringenin against different neurodegenerative disorders., Aim: We investigated the neuroprotective efficacy of naringenin against 3-nitropropionic acid (3-NP)-induced neurobehavioral, biochemical and histopathological alterations in rats., Methods: Albino Wistar rats were randomly divided into three experimental groups. Group 1, the vehicle administered group, received saline. Group 2 received 3-NP (20 mg/kg body weight, i.p. ) for 4 consecutive days. Group 3 received naringenin (50 mg/kg body weight, p.o.) twice daily for a period of 4 days, 30 min before and 6 h after the 3-NP administration. On the 5th day, neurobehavioral experiments were performed to access the behavioral outcomes and the striatum tissue was used for analysis of the monoamine oxidase (MAO) activity and serotonin (5-HT) levels. In addition, astrocytes activation was observed by glial fibrillary acidic protein (GFAP) immunostaining., Results: Our results showed that naringenin co-treatment provides neuroprotection against 3-NP-induced neurological disorders. Naringenin also increased the MAO activity and 5-HT levels in the striatum. Moreover, co-treatment with naringenin reduced the expression of GFAP protein in the striatal part and significantly attenuated the neuronal cell death. The findings of the present study suggest that naringenin provides neuroprotection and mitigates neurobehavioral alterations in experimental rats., Conclusion: The results show that co-treatment with naringenin ameliorates 3-NP-induced HD-like symptoms in rats.

Vinpocetine is a neuroprotective drug that exerts beneficial effects on neurological symptoms and cerebrovascular disease. 3-nitropropionic acid (3-NPA) is a toxin that irreversibly inhibits succinate dehydrogenase, the mitochondrial enzyme that acts in the electron transport chain at complex II. In previous studies in striatum-isolated nerve endings (synaptosomes), we found that vinpocetine decreased dopamine (DA) at expense of its main metabolite 3,4-dihydroxyphenyl-acetic acid (DOPAC), and that 3-NPA increased DA, reactive oxygen species (ROS), DA-quinone products formation, and decreased DOPAC. Therefore, in this study, the possible effect of vinpocetine on 3-NPA-induced increase in DA, ROS, lipid peroxidation, and DA-quinone products formation in striatum synaptosomes were investigated, and compared with the effects of the antioxidant α-tocopherol. Results show that the increase in DA induced by 3-NPA was inhibited by both 25 μM vinpocetine and 50 μM a-tocopherol. Vinpocetine, as a-tocopherol, also inhibited 3-NPA-induced increase in ROS (as judged by DCF fluorescence), lipid peroxidation (as judged by TBA-RS formation), and DA-quinone products formation (as judged by the nitroblue tetrazolium reduction method). As in addition to the inhibition of complex II exerted by 3-NPA, 3-NPA increases DA-oxidation products that in turn can inhibit other sites of the respiratory chain, the drop in DA produced by vinpocetine and α-tocopherol may importantly contribute to their protective action from oxidative damage, particularly in DA-rich structures. [ABSTRACT FROM AUTHOR]

Abstract: While the beneficial effects of fish oil (FO) supplements on the central nervous system function are well established, few findings have led to the hypothesis that long term n–3 polyunsaturated fatty acid (n−3 PUFA) supplements at higher doses render the membranes more susceptible to lipid peroxidation. Hence recent studies suggest the use of dietary antioxidants as adjuncts with n−3 fatty acids to effectively improve the clinical outcome in neurological disorders. In the present investigation, we examined the hypothesis, if enrichment of FO with quercetin (a natural flavonoid) can provide a higher degree of neuroprotection and tested the same in a 3-nitropropionic acid (NPA) rat model. Growing male rats administered with NPA (25mg/kg bw/d, i.p. 4days) were provided either with FO (2mL/kg bw), or Q (25mg/kg bw) or FO+Q for 14days. NPA elicited marked oxidative stress in brain (striatum and cerebellum) as evidenced by significantly enhanced ROS, malondialdehyde, protein carbonyls and nitric oxide levels. Although varying degree of protection was evident among FO or Q groups, complete normalization of oxidative markers ensued only among FO+Q rats. Further, FO+Q combination completely normalized the elevated acetylcholinesterase activity and protected against NPA‐induced mitochondrial dysfunctions. NPA induced depletion of dopamine levels was restored among all groups. Interestingly, NPA induced motor deficits were significantly improved among FO+Q rats. However, further studies are necessary to understand the mechanism/s by which FO enrichment with Q provides higher degree of protection. Nevertheless, our findings clearly suggest that the use of natural phytochemicals with moderate doses of FO may provide better neuroprotection and higher therapeutic advantage in the prevention or treatment of neurodegenerative diseases like Huntington''s disease. [Copyright &y& Elsevier]

BACKGROUND AND PURPOSE Huntington's disease is a neurodegenerative process associated with mitochondrial alterations. Inhibitors of the electron-transport channel complex II, such as 3-nitropropionic acid (3NP), are used to study the molecular and cellular pathways involved in this disease. We studied the effect of 3NP on mitochondrial morphology and its involvement in macrophagy. EXPERIMENTAL APPROACH Pharmacological and biochemical methods were used to characterize the effects of 3NP on autophagy and mitochondrial morphology. SH-SY5Y cells were transfected with GFP-LC3, GFP-Drp1 or GFP-Bax to ascertain their role and intracellular localization after 3NP treatment using confocal microscopy. KEY RESULTS Untreated SH-SY5Y cells presented a long, tubular and filamentous net of mitochondria. After 3NP (5 mM) treatment, mitochondria became shorter and rounder. 3NP induced formation of mitochondrial permeability transition pores, both in cell cultures and in isolated liver mitochondria, and this process was inhibited by cyclosporin A. Participation of the mitochondrial fission pathway was excluded because 3NP did not induce translocation of the dynamin-related protein 1 (Drp1) to the mitochondria. The Drp1 inhibitor Mdivi-1 did not affect the observed changes in mitochondrial morphology. Finally, scavengers of reactive oxygen species failed to prevent mitochondrial alterations, while cyclosporin A, but not Mdivi-1, prevented the generation of ROS. CONCLUSIONS AND IMPLICATIONS There was a direct correlation between formation of mitochondrial permeability transition pores and autophagy induced by 3NP treatment. Activation of autophagy preceded the apoptotic process and was mediated, at least partly, by formation of reactive oxygen species and mitochondrial permeability transition pores. LINKED ARTICLE This article is commented on by González-Polo et al., pp. 60-62 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02203.x [ABSTRACT FROM AUTHOR]

Abstract: 3-Nitropropionic acid (3-NP), a mitochondrial toxin, has been reported to induce an acute cochlear damage. Korean red ginseng (KRG) is known to have protective effects from some types of hearing loss. This study aimed to observe the protective effect of KRG in an ototoxic animal model using 3-NP intratympanic injection. BALB/c mice were classified into 5 groups (n =15) and dose-dependent toxic effects after intratympanic injection with 3-NP (300–5000mM) on the left ear were investigated to determine the appropriate toxicity level of 3-NP. For observation of the protective effects of KRG, 23 mice were grouped into 3-NP (500mM, n =12) and KRG+3-NP groups (300mg/kg KRG for 7 days before 500mM 3-NP administration, n =11). Auditory brain response (ABR) and cochlear morphological evaluations were performed before and after drug administration. The ABR thresholds in the 800–5000mM groups exceeded the maximum recording limit at 16 and 32kHz 1 day after 3-NP administration. The ABR threshold in the 500mM 3-NP+KRG group was significantly lower than that in the 500mM 3-NP group from post 1 week to 1 month. The mean type II fibrocyte counts significantly differed between the control and 3-NP groups and between the 3-NP and 3-NP+KRG groups. Spiral ganglion cell degeneration in the 3-NP group was more severe than that in the 3-NP+KRG group. This animal model exhibited a dose-dependent hearing loss with histological changes. KRG administration ameliorated the deterioration of hearing by 3-NP. [Copyright &y& Elsevier]

Abstract: Nuclear factor-erythroid 2-related factor-2 (Nrf2) mediated regulation of cellular antioxidant production and the anti-inflammatory mechanism play an important role in neuroprotection against neurodegenerative diseases. Naringin a citrus flavonone, has been reported to possess neuroprotective effect against Huntington’s disease, and other neurodegenerative disorders, however the mechanisms underlying its beneficial effects on 3-nitropropionic acid (3-NP)-induced neurodegeneration are poorly defined. The objective of the present study was to investigate the neuroprotective role of naringin and delineate the mechanism of action on 3-NP-induced neurodegeneration. Rats were injected with 3-NP (10mg/kg body weight/day, i.p.) for 2weeks to develop neurodegeneration, while naringin (80mg/kg body weight/day, orally) was administered throughout the experimental period, 1h prior to 3-NP exposure. Thereafter rats were euthanized for biochemical, histological, and molecular studies. Treatment with naringin ameliorated the reduced glutathione/oxidized glutathione ratio with concomitant decrease in the levels of hydroxyl radical, hydroperoxide and nitrite in 3-NP-induced rats. Nissl staining and transmission electron microscopic studies showed that naringin modulated 3-NP-induced histological changes. Naringin induces NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutathione S-transferase P1 and gamma-glutamylcysteine ligase mRNA expressions through the activation of Nrf2 and decreased the expressions of pro-inflammatory mediators like tumour necrosis factor-alpha, cyclooxygenase-2 and inducible nitric oxide synthase. These results indicate that naringin might be beneficial in mitigating 3-NP-induced neurodegeneration through the enhancement of phase II and antioxidant gene expressions via Nrf2 activation; thereby modulating the oxidative stress and inflammatory responses. [Copyright &y& Elsevier]

Abstract: Huntington''s disease (HD) is a progressive neurodegenerative disorder with a spectrum of cognitive, behavioral, and motor abnormalities. The mitochondrial toxin 3-nitropropionic acid (3-NP) effectively induces specific behavioral changes, primarily manifested as prepulse inhibition (PPI) deficit of acoustic startle stimuli, and selective striatal lesions in rats and primates mimicking those in HD. The implications of nitric oxide in a variety of neurodegenerative diseases attract attention to study the possible role of flavonoids in interaction with nitric oxide pathways involved in HD. The present study investigates the potential effect of hesperidin, a flavanone group member, on 3-NP-induced behavioral, neurochemical, histopathological and cellular changes. Systemic administration of 3-NP to rats for 5 days (20mg/kg) caused reduction of locomotor activity by days 2 and 5, 55% deficit of PPI response, elevation of cortical, striatal and hippocampal malondialdehyde (MDA) levels by 63%, 41% and 56%, reduction of respective catalase activity by 50%. Immunohistochemical staining of cortices, striata and hippocampi showed patches of iNOS positive cells. Electron microscopic ultrastructural examination showed marked mitochondrial swelling, perivascular edema and shrunken nerve cells. Pretreatment with hesperidin (100mg/kg) ahead of 3-NP prevented any changes of locomotor activity or PPI response, slightly increased cortical, striatal and hippocampal MDA levels by 10% and reduced respective catalase activity by 22%, 20% and 5%. Only few iNOS positive cells were detected in sections from rats pretreated with hesperidin which also reduced cellular abnormalities induced by 3-NP. This study suggests a potential neuroprotective role of hesperidin against 3-NP-induced Huntington''s disease-like manifestations. Such neuroprotection can be referred to its antioxidant and anti-inflammatory activities. [Copyright &y& Elsevier]

Objective: The aim of the present study was to determine the changes in the mRNA levels of neurotrophins and their receptors in the striatal tissue of mice treated with 3-nitropropionic acid (3-NP). Methods: At 1 and 48 h after the last drug administration, the mRNA expression of nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 as well as their receptors p75, TrkA, TrkB and TrkC, was evaluated using semi-quantitative (semi-Q) and real-time RT-PCR. β-actin mRNA and ribosomal 18S (18S rRNA) were tested as internal controls. Results: 3-NP treatment did not affect mRNA expression of all neurotrophins and their respective receptors equally. Also, differences in neurotrophin and receptor mRNA expression were observed between semi-Q and real-time RT-PCR. Real-time RT-PCR was more accurate in evaluating the mRNA expression of the neurotrophins than semi-Q, and 18S rRNA was more reliable than β-actin as an internal control. Conclusion: Neurotrophins and their receptors expression is differentially affected by neuronal damage produced by inhibition of mitochondrial respiration with 3-NP treatment in low, sub-chronic doses in vivo. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction plays an important role in Huntington's disease (HD). NGF gene delivery in AD patients showed an increase in brain energy metabolism and NGF has been shown neuroprotective effects against mitochondrial toxins. However, the role of NGF in regulating mitochondrial function is unclear. Here, we found that NGF-stimulated mitochondrial biogenesis in PC12 and primary neuron cells. Our results demonstrated that peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) is a downstream key target of the NGF signalling pathway. In a 3-nitropropionic acid (3-NP) cell model, NGF treatment rescued the defects in mitochondrial activity and mitochondrial membrane potential. Since NGF cannot freely cross blood–brain barrier, we found an astrocytic NGF inducer, Ganoderma lucidum (GaLu) extract. Its active constituents had potent effects on the induction of NGF in primary astrocytes. Among the identified ingredients, ganoderic acid C 2 was most effective. We further found that GaLu-conditioned media can enhance mitochondrial biogenesis in PC12 cells and preventing NGF signalling using NGF antibody or PGC-1α siRNA blocked these effects. Moreover, GaLu and ganoderic acid C 2 -conditioned media treatment attenuated mitochondrial defects in 3-NP cell model. After 3-NP-induced behavioural impairment and striatal degeneration in mice, GaLu treatment therapeutically restored the behaviour score, sensorimotor ability and neuronal loss. We found that striatal NGF, PGC-1α expression level and succinate dehydrogenase activity were recovered in GaLu-fed mice. These results suggest that the NGF-signalling pathway connected to the mitochondrial regulator, PGC-1α, expression. This signalling triggered by astrocytic NGF with small molecule inducers may offer a therapeutic strategy for HD. [ABSTRACT FROM AUTHOR]

Background: Inhibition of mitochondrial function occurs in many neurodegenerative diseases, and inhibitors of mitochondrial complexes I and II are used to model them. The complex II inhibitor, 3-nitroproprionic acid (3-NPA), kills the striatal neurons susceptible in Huntington's disease. The complex I inhibitor N-methyl-4-phenylpyridium (MPP+) and 6-hydroxydopamine (6-OHDA) are used to model Parkinson's disease. Zinc (Zn2+) accumulates after 3-NPA, 6-OHDA and MPP+ in situ or in vivo. Objective: We will investigate the role of Zn2+ neurotoxicity in 3-NPA, 6-OHDA and MPP+. Methods: Murine striatal/midbrain tyrosine hydroxylase positive, or near-pure cortical neuronal cultures, or animals were exposed to 3-NPA or MPP+ and 6-OHDA with or without neuroprotective compounds. Intracellular zinc ([Zn2+]i), nicotinamide adenine dinucleotide (NAD+), NADH, glycolytic intermediates and neurotoxicity were measured. Results: We showed that compounds or genetics which restore NAD+ and attenuate Zn2+ neurotoxicity (pyruvate, nicotinamide, NAD+, increased NAD+ synthesis, sirtuin inhibition or Zn2+ chelation) attenuated the neuronal death induced by these toxins. The increase in [Zn2+]i preceded a reduction in the NAD+/NADH ratio that caused a reversible glycolytic inhibition. Pyruvate, nicotinamide and NAD+ reversed the reductions in the NAD+/NADH ratio, glycolysis and neuronal death after challenge with 3-NPA, 6-OHDA or MPP+, as was previously shown for exogenous Zn2+. To test efficacy in vivo, we injected 3-NPA into the striatum of rats and systemically into mice, with or without pyruvate. We observed early striatal Zn2+ fluorescence, and pyruvate significantly attenuated the 3-NPA-induced lesion and restored behavioral scores. Conclusions: Together, these studies suggest that Zn2+ accumulation caused by MPP+ and 3-NPA is a novel preventable mechanism of the resultant neurotoxicity. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We previously reported the propensity of Bacopa monnieri (BM) leaf powder to modulate endogenous levels of oxidative stress markers in the brain of prepubertal mice. In this study, we tested the hypothesis that pretreatment with an alcoholic extract of BM (BME) could provide neuroprotection against 3-nitropropionic acid (3-NPA)-induced oxidative stress under in vitro and in vivo conditions. In chemical systems, BME exhibited multiple free radical scavenging ability. Further, BME pretreatment completely abolished 3-NPA-induced oxidative stress response in brain (striatum, St) mitochondria in vitro. Likewise, pretreatment of dopaminergic (N27 cell lines) cells with BME not only abrogated the generation of reactive oxygen species (ROS) levels, but also offered marked protection against 3-NPA-mediated cytotoxicity. These findings were further validated employing a 3-NPA mice model in vivo. We determined the degree of oxidative stress induction, redox status, enzymic antioxidants, protein oxidation, and cholinergic function in various brain regions of male mice provided with BME for 10 days (prophylaxis) followed by 3-NPA challenge (75 mg/kg bw/day, i.p.). BME prophylaxis completely prevented 3-NPA-induced oxidative dysfunctions in St and other brain regions. 3-NPA-induced robust elevation of oxidative markers (malondialdehyde levels, ROS generation, hydroperoxide levels and protein carbonyls) in cytosol of brain regions was predominantly abolished among mice given BME prophylaxis. Interestingly, BME prophylaxis also prevented the depletion of reduced glutathione, thiol levels, and perturbations in antioxidant enzymes caused by 3-NPA. Collectively these findings provide evidence on the significant prophylactic neuroprotective efficacy of BME in prepubertal mice brain. Based on these data, it is hypothesized that BME can serve as a useful adjuvant in protecting brain against oxidative-mediated neurodegenerative disorders involving oxidative stress conditions. [ABSTRACT FROM AUTHOR]

SUMMARY Aim The serotonin selective reuptake inhibitor fluoxetine (Flx) has tried to treat patients suffered acute ischemic stroke because of its possible neuroprotective actions. However, besides the neuroprotective effect, Flx at high concentration also induces some actions in contradiction to neuroprotection in the brain. The purpose of this study was to investigate whether Flx presents neuroprotective effect against 3-nitropropionic acid (3-NP)-induced hypoxic brain injury, and what is the most suitable dosage of Flx. Methods Mouse model was established by subacute systemic administration of 3-NP. Rotarod and pole tests were used to evaluate motor deficit. The oxidative stress and oxidative DNA damage were assessed respectively by measuring malondialdehyde and 8-hydroxydeoxyguanosine content in brain homogenates. Results According to measurements in the rotarod test, 7 days pretreatment plus 5 days treatment of Flx at low (2.5 mg/kg/day) and, to a lesser degree, medium (5 mg/kg/day) doses exerted a rapid and strong protection against the neurotoxicity induced by 3-NP, whereas Flx at high dose (10mg/kg/day) showed a much late and light effect. Similarly, in the pole test, Flx at 2.5 mg/kg/day had the strongest protective effects. Again, only Flx administration at 2.5 mg/kg/day canceled out the enhancement of malondialdehyde and 8-hydroxydeoxyguanosine in striatum following 3-NP neurotoxication. Conclusions Flx attenuated the motor deficits induced by 3-NP in a dose-dependent manner. In contrary to the high dose, Flx at the lower doses had a more remarkable effect against 3-NP insult, similar to acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Abstract: There is evidence to suggest that the neuroprotective effect of exposure of extremely low-frequency electromagnetic fields (ELF-EMF) may be due, at least in part, to the effect of these fields on neurotrophic factors levels and cell survival, leading to an improvement in behavior. This study was undertaken to investigate the neuroprotective effects of ELFEF in a rat model of 3-nitropropionic acid (3NP)-induced Huntington''s disease. Behavior patterns were evaluated, and changes in neurotrophic factor, cell damage, and oxidative stress biomarker levels were monitored in Wistar rats. Rats were given 3NP over four consecutive days (20 mg/kg body weight), whereas ELFEF (60 Hz and 0.7 mT) was applied over 21 days, starting after the last injection of 3NP. Rats treated with 3NP exhibited significantly different behavior in the open field test (OFT) and the forced swim test (FST), and displayed significant differences in neurotrophic factor levels and oxidative stress biomarkers levels, together with a neuronal damage and diminished neuronal density, with respect neuronal controls. ELFEF improved neurological scores, enhanced neurotrophic factor levels, and reduced both oxidative damage and neuronal loss in 3NP-treated rats. ELFEF alleviates 3NP-induced brain injury and prevents loss of neurons in rat striatum, thus showing considerable potential as a therapeutic tool. [Copyright &y& Elsevier]

Huntington's disease (HD) is characterized by the dysfunction of mitochondrial energy metabolism, which is associated with the functional impairment of succinate dehydrogenase (mitochondrial complex II), and pyruvate dehydrogenase (PDH). Treatment with 3-nitropropionic acid (3-NP), a potent irreversible inhibitor of succinate dehydrogenase, replicates most of the pathophysiological features of HD. In the present study, we investigated the effect of (-)schisandrin B [(-)Sch B, a potent enantiomer of schisandrin B] on 3-NP-induced cell injury in rat differentiated neuronal PC12 cells. The 3-NP caused cell necrosis, as assessed by lactate dehydrogenase (LDH) leakage, and mitochondrion-dependent cell apoptosis, as assessed by caspase-3 and caspase-9 activation, in differentiated PC12 cells. The cytotoxicity induced by 3-NP was associated with a depletion of cellular reduced glutathione (GSH) as well as the activation of redox-sensitive c-Jun N-terminal kinase (JNK) pathway and the inhibition of PDH. (-)Sch B pretreatment (5 and 15 μM) significantly reduced the extent of necrotic and apoptotic cell death in 3-NP-challenged cells. The cytoprotection afforded by (-)Sch B pretreatment was associated with the attenuation of 3-NP-induced GSH depletion as well as JNK activation and PDH inhibition. (-)Sch B pretreatment enhanced cellular glutathione redox status and ameliorated the 3-NP-induced cellular energy crisis, presumably by suppressing the activated JNK-mediated PDH inhibition, thereby protecting against necrotic and apoptotic cell death in differentiated PC12 cells. [ABSTRACT FROM AUTHOR]

Abstract: Huntington''s disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD seem to be related to oxidative stress, excitotoxicity and misbalance in energetic metabolism. In this study we evaluated the potential relationship between energetic impairment, excitotoxicity and oxidative stress in rat striatal slices exposed to quinolinic acid (QA; as an excitotoxic model), 3-nitropropionic acid (3-NP; as an inhibitor of mitochondrial succinate dehydrogenase), as well as a combined model produced by the co-administration of these two toxins at subtoxic concentrations. We took advantage of the direct antioxidant/scavenger properties of Probucol in order to investigate the role of reactive oxygen species (ROS) in mediating the toxicity of both compounds alone or in association. Experiments with MK-801 (a NMDA type glutamate receptor antagonist) and succinate (an energy precursor agent) were also performed in an attempt to better comprehend the mechanisms of damage and neuroprotection. QA (1mM), 3-NP (1mM) and QA plus 3-NP (0.1mM of both) significantly induced mitochondrial dysfunction and produced an increase in ROS generation, as well as a significant increase in lipid peroxidation in striatal slices. Probucol (10 and 30μM) prevented ROS formation and lipid peroxidation in all used models, but did not protect against the mitochondrial dysfunction induced by 3-NP (only by QA or QA plus 3-NP). Sodium succinate (1mM) protected the striatal slices only against 3-NP-induced mitochondrial dysfunction. On the other hand, MK-801 protected against mitochondrial dysfunction in all used models. Our data suggest that the two studied toxic models (QA and 3-NP) or the combined model (QA plus 3-NP) can generate complex patterns of damage, which involve metabolic compromise, ROS formation, and oxidative stress. Moreover, a partial inhibition of SDH by subtoxic 3-NP and moderate excitotoxicty by subtoxic QA are potentiated when both agents are associated. The toxic action of QA plus 3-NP seems to be involved with Ca2+ metabolism and ROS formation, and can be prevented or attenuated by antioxidant/scavenger compounds and NMDAr antagonists. [Copyright &y& Elsevier]

Mitochondrial dysfunction is a major event involved in the pathogenesis of Huntington's disease (HD). The present study evaluates the role of N-acetyl-L-cysteine (NAC) in preventing mitochondrial dysfunctions in a 3-nitropropionic acid (3-NP)-induced model of HD. Administration of 3-NP to rats (Wistar strain) resulted in significant inhibition of mitochondrial complexes II, IV and V in the striatum. However, no significant effect on complex I was observed. Increased generation of reactive oxygen species and lipid peroxidation was observed in mitochondria of 3-NP-treated animals. Endogenous antioxidants (thiols and manganese-superoxide dismutase) were lowered in mitochondria of 3-NP-treated animals. 3-NP-treated animals showed increased cytosolic cytochrome c levels and mitochondrial swelling. Increased expressions of caspase-3 and p53 were also observed in 3-NP-treated animals. Histopathological examination of the striata of 3-NP-treated animals revealed increased neural space, neurodegeneration and gliosis. This was accompanied by cognitive and motor deficits. NAC treatment, on the other hand, was found to be effective in reversing 3-NP-induced mitochondrial dysfunctions and neurobehavioral deficits. Our findings suggest a beneficial effect of NAC in HD. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The present study was undertaken to assess the neuroprotective effects of aqueous extract of Garcinia kola on neurotoxin administered malnourished mice. The study was carried out using thirty-two adult Malnourished mice which were randomly assigned into four groups (n=8): A, B, C, and D. Group A served as control, while the other groups served as the experimental groups. Animals in group A were fed malnourished diet ad libitum and water given liberally. Animals in group B were administered with 3- Nitropropionic acid (3-NP) (neurotoxin) only (20 mg/kg body weight), group C were given only Garcinia kola extracts, and group D were pre-treated with Garcinia kola extracts for seven days (200mg/kg) prior to administration of neurotoxin (20 mg/kg body weight). After three days of neurotoxins administration in the relevant groups, the brains were excised and fixed in formal calcium for histological processing. The study showed that hippocampal and cerebellar neurons of animals in group B exhibited some cellular degeneration and blood vessel blockage, which were not seen in groups A, C and D. Cresyl violet staining was least intense in group B than in groups A, C and D. Despite the fact that animals in group D has equal administration of 3-Nitropropionic acid concentration, there were no traces of neural degeneration as it was evidenced in group B. It was concluded that Garcinia kola has protective effects on the neurons of the hippocampus and cerebellum of malnourished mice. [ABSTRACT FROM AUTHOR]

Abstract: Huntington''s disease is a progressive neurodegenerative disorder that gradually reduces memory, cognitive skills and normal movements of affected individuals. Systemic administration of 3-Nitropropionic acid induces selective striatal lesions in rodents and non-human primates. Therefore, the present study has been designed to elucidate the comparative mechanistic profile of gabapentin, lamotrigine and their interactions with GABAergic modulators against 3-Nitropropionic acid induced neurotoxicity. Systemic 3-Nitropropionic acid (10mg/kg) administration for 14days significantly reduced body weight, locomotor activity, grip strength, oxidative defense (LPO, nitrite, SOD and catalase) and impaired mitochondrial complex enzyme (I, II, IV and MTT assay) activities in the striatum. 3-Nitropropionic acid treatment also increased TNF-α level in the striatum. Gabapentin (50 and 100mg/kg) and lamotrigine (10, 20 and 40mg/kg) treatments significantly restored behavioural, oxidative defense and mitochondrial complex enzyme activities and proinflammatory markers (TNF-α) as compared to 3-Nitropropionic acid treated group. Systemic picrotoxin (1mg/kg) pretreatment with sub effective dose of gabapentin (50mg/kg) or lamotrigine (20mg/kg) significantly attenuated their protective effect. Further, GABA (50mg/kg) and/or muscimol (0.05mg/kg) pretreatment with sub effective dose gabapentin (50mg/kg) and lamotrigine (20mg/kg) significantly potentiated their protective effects which were significant as compared to their effect alone. The results of the present study suggest that a GABAergic mechanism is involved in the protective effect of gabapentin and lamotrigine against 3-Nitropropionic acid induced neurotoxicity. [Copyright &y& Elsevier]

Abstract: MicroRNAs (miR) are single-stranded short RNA molecules that regulate gene expression by degradation or translational repression of mRNA. It has been reported that the downregulation of miR-199a plays an important role in cardiac ischemic tolerance. We examined the expression of miR-199a after 3-nitropropionic acid (3-NPA) preconditioning in rat brain. 3-NPA (20mg/kg), an irreversible inhibitor of succinate dehydrogenase, was injected intraperitoneally to induce ischemic tolerance in rats. For comparison, the control group received intraperitoneal injections of vehicle (0.9% sodium chloride). Quantitative RT-PCR assay was applied to detect the expression of miR-199a. Luciferase reporter assays and Western blotting were used to verify the target genes of miR-199a. In cortex and striatum, miR-199a was downregulated at two separate time intervals (the 2nd and 4th day), while in the hippocampus, it was downregulated on the 2nd day after 3-NPA preconditioning. The maximum reduction of miR-199a was 66.3% in striatum (4th day), 54.9% in hippocampus (2nd day), and 27.6% in cortex (2nd day). The level of sirt1 protein, a putative target of miR-199a and a known mediator of neuroprotective effect in brain ischemic tolerance, decreased significantly in hippocampal neurons by overexpression of miR-199a, while it increased with knockdown of miR-199a. Taking these results together, we hypothesize miR-199a may have a role in the formation of cerebral ischemic tolerance. [Copyright &y& Elsevier]

Abstract: Peroxisome proliferators activated receptor is regarded as potential therapeutic targets to control various neurodegenerative disorders. However, none of the study has elucidated its effect in the treatment of Huntington''s disease. We explored whether peroxisome proliferators activated receptor-α agonist may attenuate various behavioral and biochemical alterations induced by systemic administration of 3-nitropropionic acid (3-NP), an accepted experimental animal model of Huntington''s disease phenotype. Intraperitoneal administration of 3-NP (20mg/kg., i.p.) for 4days in rats produced hypolocomotion, muscle incoordination, and cognitive dysfunction. Daily treatment with fenofibrate (100 or 200mg/kg., p.o.), 30min prior to 3-NP administration for a total of 4days, significantly improved the 3-NP induced motor and cognitive impairment. Biochemical analysis revealed that systemic 3-NP administration significantly increased oxidative and nitrosative stress (increase lipid peroxidation, protein carbonyls and nitrite level), lactate dehydrogenase activity whereas, decreased the activities of catalase, superoxide dismutase, reduced glutathione, and succinate dehydrogenase. Fenofibrate treatment significantly attenuated oxidative damage, cytokines and improved mitochondrial complexes enzyme activity in brain. In the present study, MK886, a selective inhibitor of peroxisome proliferators activated receptor-α was employed to elucidate the beneficial effect through either receptor dependent or receptor independent neuroprotective mechanisms. Administration of MK886 (1mg/kg, i.p.) prior to fenofibrate (200mg/kg, p.o.) abolished the effect of fenofibrate. The results showed that receptor dependent neuroprotective effects of fenofibrate in 3-NP administered rats provide a new evidence for a role of PPAR-α activation in neuroprotection that is attributed by modulating oxidative stress and inflammation. [Copyright &y& Elsevier]

Abstract: The aim of this study was to investigate the protective effect of naringin, a flavonoid on 3-Nitropropionic acid (3-NP)-induced neurodegeneration through the modulation of intrinsic apoptotic cascade in Wistar rats. 3-NP is an irreversible inhibitor of complex II in the mitochondria. 3-NP-induced neurodegeneration has been widely used as an animal model of Huntington’s disease (HD). Increased oxidative stress is one of the major deleterious events in 3-NP-induced neuronal apoptosis. Rats administered with 3-NP showed increase in the levels of lipid peroxidation and protein carbonyl, which was significantly decreased upon naringin treatment (80mg/kg body weight). 3-NP-induced rats showed decrease in the activities of enzymic antioxidants and reduced levels of non-enzymic antioxidants. Naringin treatment ameliorated the antioxidant status by increasing the activities of enzymic antioxidants and the levels of non-enzymatic antioxidants. 3-NP-induced rats showed decrease in the activities of ATPases in striatum, which was restored to normal level upon naringin treatment. Histopathological observation of the striatal tissue showed protective role of naringin in 3-NP-induced rats. Naringin also reduced the 3-NP-induced apoptosis via decrease in the cytochrome c release from mitochondria and caspase 3 activation as revealed by Western blot. Naringin treatment also decreased the expressions of pro-apoptotic markers like Bad and Bax. Further, naringin antagonized 3-NP-induced decrease in Bcl-2 mRNA expression. The results of this study show evidence on the neuroprotective effect of naringin against 3-NP-induced neuronal apoptosis through its antioxidant and anti-apoptotic effects. [Copyright &y& Elsevier]

Abstract: Although terminally differentiated neurons lack the capacity to undergo cell division, they retain the capacity to reactivate the cell cycle. This reactivation, however, has been linked to the degeneration of neurons in many experimental models of neurodegenerative disease and in post-mortem brains of affected patients. Expression of markers of the G1 phase and apoptotic neurons has been detected in the striatal lesion of rats treated with 3-nitropropionic acid (3-NPA). Here we examined whether neuronal apoptosis induced by 3-NPA was mediated by the reactivation of the cell cycle. To this end, we studied whether TUNEL-positive neurons expressed the G1-phase markers cyclin-dependent kinase 4 (CDK4) and cyclin D (CyD). In addition, we also evaluated the neuronal expression of pRb and Ki67 antigens, both of which are involved in the regulation of cell-cycle progression. In 3-NPA-treated rats, CDK4 and CyD were not detected in TUNEL-positive neurons, but they were expressed in neurons in the core of the lesion, which were assumed to be in a more advanced stage of degeneration, since they had weaker NeuN staining and lacked Hoechst staining. In addition, injured neurons in the striatal lesion of 3-NPA-treated rats had lost the constitutive expression of pRb and Ki67 that we had detected in control animals. Taken together, these results indicate that neuronal apoptosis in the striatal lesion of 3-NPA-treated rats was not triggered by cell-cycle re-entry, and we conclude that expression of G1 markers may be considered an aberrant survival response, with no relation to the mechanisms of apoptosis. [Copyright &y& Elsevier]

Abstract: Huntington’s disease (HD) is a genetic neurodegenerative disorder characterized by striatal neurodegeneration, involving apoptosis. FK506, an inhibitor of calcineurin (or protein phosphatase 3, formerly known as protein phosphatase 2B), has shown neuroprotective effects in several cellular and animal models of HD. In the present study, we show the protective effects of FK506 in two striatal HD models, primary rat striatal neurons treated with 3-nitropropionic acid (3-NP) and immortalized striatal STHdh cells derived from HD knock-in mice expressing normal (STHdh 7/7) or full-length mutant huntingtin (FL-mHtt) with 111 glutamines (STHdh 111/111), under basal conditions and after exposure to 3-NP or staurosporine (STS). In rat striatal neurons, FK506 abolished 3-NP-induced increase in caspase-3 activation, DNA fragmentation/condensation and necrosis. Nevertheless, in STHdh 111/111 cells under basal conditions, FK506 did not prevent, in a significant manner, the release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria, or alter Bax/Bcl-2 ratio, but significantly reverted caspase-3 activation. In STHdh 111/111 cells treated with 0.3mM 3-NP or 25 nM STS, linked to high necrosis, exposure to FK506 exerted no significant effects on caspase-3 activation. However, treatment of STHdh 111/111 cells exposed to 10nM STS with FK506 effectively prevented cell death by apoptosis and moderate necrosis. The results suggest that FK506 may be neuroprotective against apoptosis and necrosis under mild cell death stimulus in the presence of FLmHtt. [Copyright &y& Elsevier]

Huntington’s disease (HD) is characterized by progressive degeneration of neurons in the striatum, cortex and other parts of the brain, causing motor and cognitive dysfunction. 3-Nitropropionic acid (3-NP) is a well-known mycotoxin that significantly induces motor dysfunction in animals. Studies suggested the involvement of oxidative stress and nitric oxide mechanisms in HD pathogenesis. Clinical reports have also indicated the neuroprotective potential of antidepressants. Therefore, the present study has been designed to elucidate and compare the mechanistic role of different antidepressants (sertraline, venlafaxine, imipramine and trazodone) and their interaction with nitric oxide modulators if any, against 3-NP-induced neurotoxicity. Systemic 3-NP (10 mg/kg) administration for 14 days significantly reduced locomotor activity, body weight, motor coordination, oxidative defense and impaired mitochondrial complex enzyme activities in the striatum. Sertraline, venlafaxine, imipramine and trazodone treatments significantly improved behavioral, oxidative defense and mitochondrial complex enzyme activities as compared with the 3-NP-treated group. Systemic L-arginine (50 mg/kg) pretreatment with sub-effective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) and trazodone (10 mg/kg) for 14 days significantly attenuated their protective effect. Similarly, L-nitro-arginine methyl ester (L-NAME) (10 mg/kg) pretreatment with sub-effective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) and trazodone (10 mg/kg) for 14 days significantly potentiated their protective effects which were significant as compared with their effect alone, respectively. The results of the present study suggest that a nitric oxide mechanism might be involved in their protective effect against 3-NP-induced neurotoxicity. [ABSTRACT FROM PUBLISHER]

Aims: 3-Nitropropionic acid (3-NPA) is a natural toxin that, when administered to experimental animals, reproduces the brain lesions observed in Huntington's disease, which mainly consist of selective neurodegeneration of the striatum. The lesions also include severe alterations to the blood-brain barrier (BBB), which increase its permeability to several substances including blood components and exogenous fluorescent dyes, and the concomitant degradation of some of its constituents such as endothelial cells, tight junction proteins and the basement membrane. We studied here the role of matrix metalloproteinases (MMPs)-2 and -9, also called gelatinases A and B, in the degradation of the BBB in the striatal lesions induced by the systemic administration of 3-NPA to Sprague-Dawley rats. Methods: 3-NPA was intraperitoneally administered at a dose of 20 mg/kg once a day for 3 days. MMPs were studied by means of immunohistochemistry and in situ zymography. Results: In 3-NPA-treated rats, MMP-9 was present in most of the degraded blood vessels in the injured striatum, while it was absent in vessels from noninjured tissue. In the same animals, MMP-2 staining was barely detected close to degraded blood vessels. The combination of MMP-9 immunostaining, in situ zymography and inhibitory studies of MMP-9 confirmed that net gelatinolytic activity detected in the degraded striatal blood vessels could be attributed almost exclusively to the active form of MMP-9. Conclusion: Our results highlight the prominent role of MMP-9 in BBB disruption in the striatal injured areas of this experimental model of Huntington's disease. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To assess the neuroprotective effects of aqueous extract of Garcinia kola on neurotoxin administered malnourished mice adopting histological procedure. Methods: The study was carried out using thirty-two adult malnourished mice which were randomly assigned into four groups (n=8): A, B, C and D. Group A served as control, while the other groups served as the experimental groups. Animals in group A were fed malnourished diet ad libitum and given water liberally. Animals in group B were administered with 3-Nitropropionic acid (3-NP) (neurotoxin) only at 20 mg/kg body weight, group C were given only Garcinia kola extracts, and group D were pre-treated with Garcinia kola extracts at 200 mg/kg for seven days prior to administration of neurotoxin at 20 mg/kg body weight. After three days of neurotoxins administration in the relevant groups, the brains were excised and fixed in formal calcium for histological processing. Results: The study showed that hippocampal and cerebellar neurons of animals in group B exhibited some cellular degeneration and blood vessel blockage, which were not seen in groups A, C and D. Cresyl violet staining was least intense in group B than in groups A, C and D. Despite the fact that animals in group D has equal administration of 3-Nitropropionic acid concentration, there were no traces of neural degeneration as it was evidenced in group B. Conclusions: It is concluded that Garcinia kola has protective effects on the neurons of the hippocampus and cerebellum of malnourished mice. [Copyright &y& Elsevier]

Aims: Recent studies suggest that sub-lethal ischemia protects the brain against subsequent ischemic injury. In this study, the nature of changes in the blood brain barrier permeability and brain edema following transient middle cerebral artery ischemia and 3-nitropropionic acid was evaluated. Materials & Methods: This clinical trial was carried out in Islamic Azad University of Zanjan in summer 2010. Rats were divided into 6 main experimental groups, each containing 28 animals. The first group (model of ischemic preconditioning) was subjected to 10 minutes of transient middle cerebral artery occlusion in the first day and was subjected to 60 minutes of middle cerebral artery occlusion in the second day. The second group (controls) did not receive any intervention except a 60-minute middle cerebral artery occlusion in the second day. The third group (sham) was only subjected to 10 minutes of transient middle cerebral artery occlusion in the first day. The fourth group (intact) was not subjected to any intervention. The fifth group (model of 3- nitropropionic acid preconditioning) received a single dose of 20mg/kg 3-nitropropionic acid in the first day and was subjected to 60 minutes of middle cerebral artery occlusion. The sixth group (control) received normal saline in the first day and a 60-minute middle cerebral artery occlusion in the second day. In the third day, the infarct volume, blood brain barrier permeability and brain edema was evaluated in the groups. Data was analyzed by SPSS 12 software by LSD method. Results: Preconditioning with transient ischemia and 3-nitropropionic acid decreased neurologic deficit scores, infarct volume, brain barrier permeability and brain edema. Conclusion: Transient ischemia and 3-nitropropionic acid are associated with decrease in neurologic deficit scores, infarct volume, blood brain barrier's permeability and brain edema; therefore, play active role in ischemic protection. [ABSTRACT FROM AUTHOR]