Injection Of 3-nitropropionic Acid Research Articles

Azilsartan Attenuates 3-Nitropropinoic Acid-Induced Neurotoxicity in Rats: The Role of IĸB/NF-ĸB and KEAP1/Nrf2 Signaling Pathways

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by motor, psychiatric and cognitive symptoms. Injection of 3-nitropropionic acid (3-NP) is a widely used experimental model for induction of HD. The current study aimed to inspect the potential neuroprotective properties of azilsartan (Azil), an angiotensin II type 1 receptor blocker (ATR1), in 3-NP-induced striatal neurotoxicity in rats. Rats were randomly allocated into five groups and treated for 14 days as follows: group I received normal saline; group II received Azil (10 mg/kg, p.o.); group III received 3-NP (10 mg/kg, i.p); group IV and V received Azil (5 or 10 mg/kg, p.o, respectively) 1 h prior to 3-NP injection. Both doses of Azil markedly attenuated motor and behavioural dysfunction as well as striatal histopathological alterations caused by 3-NP. In addition, Azil balanced striatal neurotransmitters levels as evidenced by the increase of striatal gamma-aminobutyric acid content and the decrease of glutamate content. Azil also amended neuroinflammation and oxidative stress via modulating IĸB/NF-ĸB and KEAP1/Nrf2 downstream signalling pathways, as well as reducing iNOS and COX2 levels. Moreover, Azil demonstrated an anti-apoptotic activity by reducing caspase-3 level and BAX/BCL2 ratio. In conclusion, the present study reveals the neuroprotective potential of Azil in 3-NP-induced behavioural, histopathological and biochemical changes in rats. These findings might be attributed to inhibition of ATR1/NF-κB signalling, modulation of Nrf2/KEAP1 signalling, anti-inflammatory, anti-oxidant and anti-apoptotic properties.Graphical

Kaempferol prevents the activation of complement C3 protein and the generation of reactive A1 astrocytes that mediate rat brain degeneration induced by 3-nitropropionic acid

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.

Ginsenoside Rg1 exerts neuroprotective effects in 3-nitropronpionic acid-induced mouse model of Huntington's disease via suppressing MAPKs and NF-κB pathways in the striatum.

Huntington's disease (HD) is one of main neurodegenerative diseases, characterized by striatal atrophy, involuntary movements, and motor incoordination. Ginsenoside Rg1 (Rg1), an active ingredient in ginseng, possesses a variety of neuroprotective effects with low toxicity and side effects. In this study, we investigated the potential therapeutic effects of Rg1 in a mouse model of HD and explored the underlying mechanisms. HD was induced in mice by injection of 3-nitropropionic acid (3-NP, i.p.) for 4 days. From the first day of 3-NP injection, the mice were administered Rg1 (10, 20, 40 mg·kg-1, p.o.) for 5 days. We showed that oral pretreatment with Rg1 alleviated 3-NP-induced body weight loss and behavioral defects. Furthermore, pretreatment with Rg1 ameliorated 3-NP-induced neuronal loss and ultrastructural morphological damage in the striatum. Moreover, pretreatment with Rg1 reduced 3-NP-induced apoptosis and inhibited the activation of microglia, inflammatory mediators in the striatum. We revealed that Rg1 exerted neuroprotective effects by suppressing 3-NP-induced activation of the MAPKs and NF-κΒ signaling pathways in the striatum. Thus, our results suggest that Rg1 exerts therapeutic effects on 3-NP-induced HD mouse model via suppressing MAPKs and NF-κΒ signaling pathways. Rg1 may be served as a novel therapeutic option for HD.

Hyperpolarization of the subthalamic nucleus alleviates hyperkinetic movement disorders

Modulation of subthalamic nucleus (STN) firing patterns with injections of depolarizing currents into the STN is an important advance for the treatment of hypokinetic movement disorders, especially Parkinson’s disease (PD). Chorea, ballism and dystonia are prototypical examples of hyperkinetic movement disorders. In our previous study, normal rats without nigro-striatal lesion were rendered hypokinetic with hyperpolarizing currents injected into the STN. Therefore, modulation of the firing pattern by injection of a hyperpolarizing current into the STN could be an effective treatment for hyperkinetic movement disorders. We investigated the effect of injecting a hyperpolarizing current into the STNs of two different types of hyperkinetic animal models and a patient with an otherwise uncontrollable hyperkinetic disorder. The two animal models included levodopa-induced hyperkinetic movement in parkinsonian rats (L-DOPA-induced dyskinesia model) and hyperkinesia induced by an intrastriatal injection of 3-nitropropionic acid (Huntington disease model), covering neurodegeneration-related as well as neurotoxin-induced derangement in the cortico-subcortical re-entrant loops. Delivering hyperpolarizing currents into the STN readily alleviated the hyperkinetic behaviors in the two animal models and in the clinical case, with an evident increase in subthalamic burst discharges in electrophysiological recordings. Application of a hyperpolarizing current into the STN via a Deep brain stimulation (DBS) electrode could be an effective general therapy for a wide spectrum of hyperkinetic movement disorders.

Evidence for a Role of Second Pathophysiological Stress in Prevention of Delayed Neuronal Death in the Hippocampal CA1 Region

In ischemic tolerance experiment, when we applied 5-min ischemia 2 days before 30-min ischemia, we achieved a remarkable (95.8%) survival of CA1 neurons. However, when we applied 5-min ischemia itself, without following lethal ischemia, we found out 45.8% degeneration of neurons in the CA1. This means that salvage of 40% CA1 neurons from postischemic degeneration was initiated by the second pathophysiological stress. These findings encouraged us to hypothesize that the second pathophysiological stress used 48 h after lethal ischemia can be efficient in prevention of delayed neuronal death. Our results demonstrate that whereas 8 min of lethal ischemia destroys 49.9% of CAI neurons, 10 min of ischemia destroys 71.6% of CA1 neurons, three different techniques of the second pathophysiological stress are able to protect against both: CA1 damage as well as spatial learning/memory dysfunction. Bolus of norepinephrine (3.1 micromol/kg i.p.) used two days after 8 min ischemia saved 94.2%, 6 min ischemia applied 2 days after 10 min ischemia rescued 89.9%, and an injection of 3-nitropropionic acid (20 mg/kg i.p.) applied two days after 10 min ischemia protected 77.5% of CA1 neurons. Thus, the second pathophysiological stress, if applied at a suitable time after lethal ischemia, represents a significant therapeutic window to opportunity for salvaging neurons in the hippocampal CA1 region against delayed neuronal death.

Effect of nicotine on 3-nitropropionic acid-induced oxidative stress in synaptosomes

In this paper, the effect of nicotine on the oxidative changes produced by 3-nitropropionic acid (20 mg/kg i.p./day for 4 days) in striatal and cortical synaptosomes of Wistar rats was studied. The effects of 3-nitropropionic acid were evaluated as changes in the quantity of protein carbonyl groups, lipid peroxidation products, superoxide distumase activity and reduced succinate dehydrogenase activity. All changes were prevented by the pre-injection of nicotine (1.5 mg/kg i.p./day), beginning 4 days before and continuing for 4 days after the first injection of 3-nitropropionic acid. These findings indicate that: (i) 3-nitropropionic acid induces a state of oxidative stress in cortical and striatal synaptosomes and (ii) nicotine prevents oxidative stress induced by 3-nitropropinonic acid. In conclusion, the results show the ability of nicotine to modify neural response to 3-nitropropionic acid with the protective mechanism likely involving the antioxidative processes of nicotine.

Effects of Sertoli cell transplants in a 3-nitropropionic acid model of early Huntington's disease: a preliminary study.

Problems with immunosuppression and graft survival limit clinical applications of neurotransplantation protocols for neurodegenerative disease. Sertoli cells, testes-derived cells with immunosuppressive and trophic properties, may serve as an alternative cell source for transplantation. Sertoli cells were transplanted into the striatum of rats following two injections of 3-nitropropionic acid (3-NP) to determine whether they could ameliorate abnormalities in a model of early stage Huntington's disease. 3-NP-induced locomotor hyperactivity was significantly reduced in rats receiving Sertoli transplants compared to controls, with some behaviors returning to baseline. Sertoli cells survived in the striatum without systemic immunosuppression and some formed tubule-like structures. These results show that Sertoli transplants are able to ameliorate locomotor abnormalities in a 3-NP model of early HD. Thus, Sertoli cells should be further evaluated as a possible treatment strategy for the early stages of Huntington's disease.