losartan-potassium and 3-nitropropionic-acid

Oxidative stress and mitochondrial dysfunction are among the mechanisms expected to explain the pathogenesis of Huntington's disease. Erythropoietin (EPO) and the Bacillus Calmette-Guérin (BCG) vaccine have neuroprotective effects against neurodegenerative diseases; however, the full mechanisms of their action are currently unclear. Here, for the first time, we investigated the neuroprotective effect of BCG vaccination in Huntington-like disease induced by 3-nitropropionic acid (3-NP) and its combination with EPO. Male Wistar rats were randomized into five groups: saline-treated control; 3-NP group (20 mg/kg/day, i.p.) for 7 days; EPO-treated group (5000 IU/kg/day, i.p.) for 14 days after 3-NP administration; live BCG vaccine prophylactic group (5000 cfu/g, i.p.) 10 days prior to 3-NP administration; and live BCG vaccine (5000 cfu/g, i.p.) 10 days before 3-NP administration, followed by EPO treatment (5000 IU/kg/day, i.p.) for 14 days. In a histopathological examination, striatum neurodegeneration was evidenced in the 3-NP injected rats. Administration of 3-NP elevated the levels of p-PI3K, p-Akt, p-mTOR, p-P70S6K, BAX, malondialdehyde, nitric oxide, and cytochrome oxidase while reduced the levels of BCL-2, superoxide dismutase, reduced glutathione, and the autophagy marker microtubule-associated protein light chain 3 in the striatum. EPO and BCG ameliorated the biochemical, histopathological, and behavioral derangements induced by 3-NP, with prominent neuroprotection observed in rats administered the BCG prophylactic combined with EPO treatment. These results highlight the role played by EPO and BCG in the management of 3-NP-induced Huntington-like disease by inhibiting the PI3K/Akt/mTOR/P70S6K pathway and enhancing the autophagy.

Topics: Animals; Autophagy; BCG Vaccine; Erythropoietin; Huntington Disease; Male; Neuroprotective Agents; Nitro Compounds; Phosphatidylinositol 3-Kinases; Propionates; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Ribosomal Protein S6 Kinases, 70-kDa; TOR Serine-Threonine Kinases; Vaccination

3-Nitropropionic acid (3-NP) model serves as a beneficial tool to evaluate the effect of novel treatments for Huntington's disease (HD). The aim of the present study was to demonstrate the neuroprotective effect of recombinant human erythropoietin (rhEPO) and interferon-beta-1b (IFN-β-1b) in 3-NP-induced neurotoxicity in rats. Rats were injected with 3-NP (10 mg/kg/day, i.p) for 2 weeks and were divided into five subgroups; the first served as the HD group, the second received rhEPO (5000 IU/kg/every other day, i.p.) for 2 weeks, the third received rhEPO starting from the 5th day of 3-NP injection, the fourth received IFN-β-1b (300,000 units, every day other day, s.c) for 2 weeks, and the last received IFN-β-1b starting from the 5th day of 3-NP injection. All treatments significantly improved motor and behavior performance of rats. Moreover, all treatments markedly restored mitochondrial function as well as brain-derived neurotrophic factor level, and reduced oxidative stress biomarkers, pro-inflammatory mediators, nuclear factor kappa B expression, caspase-3, and Bax/Bcl2 ratio in the striatum. In conclusion, the present study demonstrates the neuroprotective potential of rhEPO or IFN-β-1b on 3-NP-induced neurotoxicity in rats. Furthermore, our study suggests that activation of JAK2/STAT3 or JAK1/STAT3 may contribute to the neuroprotective activity of rhEPO or IFN-β-1b, respectively. We also found that early treatment with rhEPO did not confer any benefits compared with late rhEPO treatment, while early IFN-β-1b showed a marked significant benefit compared with late IFN-β-1b.

Topics: Animals; Erythropoietin; Humans; Interferon beta-1b; Neuroprotective Agents; Nitro Compounds; Propionates; Rats; Rats, Wistar; Signal Transduction

Multiple system atrophy is a rapidly progressive neurodegenerative disorder with a markedly reduced life expectancy. Failure of symptomatic treatment raises an urgent need for disease-modifying strategies. We have investigated the neuroprotective potential of erythropoietin in (proteolipid protein)-α-synuclein transgenic mice exposed to 3-nitropropionic acid featuring multiple system atrophy-like pathology including oligodendroglial α-synuclein inclusions and selective neuronal degeneration. Mice were treated with erythropoietin starting before (early erythropoietin) and after (late erythropoietin) intoxication with 3-nitropropionic acid. Nonintoxicated animals receiving erythropoietin and intoxicated animals treated with saline served as control groups. Behavioral tests included pole test, open field activity, and motor behavior scale. Immunohistochemistry for tyrosine hydroxylase and dopamine and cyclic adenosine monophosphate-regulated phosphoprotein (DARPP-32) was analyzed stereologically. Animals receiving erythropoietin before and after 3-nitropropionic acid intoxication scored significantly lower on the motor behavior scale and they performed better in the pole test than controls with no significant difference between early and late erythropoietin administration. Similarly, rearing scores were worse in 3-nitropropionic acid-treated animals with no difference between the erythropoietin subgroups. Immunohistochemistry revealed significant attenuation of 3-nitropropionic acid-induced loss of tyrosine hydroxylase and DARPP-32 positive neurons in substantia nigra pars compacta and striatum, respectively, in both erythropoietin-treated groups without significant group difference in the substantia nigra. However, at striatal level, a significant difference between early and late erythropoietin administration was observed. In the combined (proteolipid protein)-α-synuclein 3-nitropropionic acid multiple system atrophy mouse model, erythropoietin appears to rescue dopaminergic and striatal gabaergic projection neurons. This effect is associated with improved motor function. Further studies are warranted to develop erythropoietin as a potential interventional therapy in multiple system atrophy.

Topics: alpha-Synuclein; Animals; Cell Death; Convulsants; Corpus Striatum; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Drug Administration Schedule; Erythropoietin; Exploratory Behavior; Humans; Mice; Mice, Transgenic; Motor Activity; Multiple System Atrophy; Myelin Proteolipid Protein; Nitro Compounds; Propionates; Substantia Nigra; Tyrosine 3-Monooxygenase

Brain-derived neurotrophic factor (BDNF) deficiency and mitochondrial dysfunction have been implicated in the pathogenesis of Huntington's disease (HD). 3-Nitropropionic acid (3-NP) is a mitochondrial inhibitor commonly used as a pharmacological model mimicking HD. We have recently reported that preconditioning of primary rat cortical cultures with BDNF induces sonic hedgehog (SHH), which contributes to the protective effects of BDNF against 3-NP neurotoxicity. Because carbamylated erythropoietin (EPO) may induce SHH, we investigated whether BDNF-dependent SHH expression and 3-NP resistance require prior induction of EPO. We found that BDNF induced EPO expression at both mRNA and protein levels. BDNF-mediated SHH induction and 3-NP resistance were abolished by the soluble EPO receptor (sEPO-R), an EPO inhibitor. Recombinant rat EPO (rEPO) induced SHH and attenuated 3-NP neurotoxicity. The rEPO-dependent neuroprotection was suppressed by the SHH inhibitor cyclopamine (CPM); however, sEPO-R failed to affect SHH neuroprotection. Furthermore, the rEPO-dependent neuroprotection was not suppressed by the BDNF neutralizing antibody, which completely abolished BDNF-mediated 3-NP resistance at the same dosage. Overall, our results demonstrate that BDNF-dependent SHH expression and 3-NP resistance require prior induction of EPO, thus establishing a signaling cascade of "BDNF-->EPO-->SHH-->3-NP resistance" in rat cortical neurons.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cells, Cultured; Cerebral Cortex; Drug Resistance; Erythropoietin; Feedback, Physiological; Hedgehog Proteins; Mitochondria; Neurons; Neuroprotective Agents; Nitro Compounds; Propionates; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Signal Transduction

To examine the changes in erythropoietin (Epo) protein and its mRNA expression in rat brain subjected to focal ischemia and possible mechanism of the preconditioning of mitochondrial toxin 3-nitropropionic acid (3-NPA), rats were administrated either vehicle or 3-NPA at a dose of 20 mg/kg, intraperitoneally (ip), 3 days prior to a 2-h middle cerebral artery occlusion followed by 24-h reperfusion. Infarct volumes were measured by using 2, 3, 5 triphenylte trazolinm chloride (TTC) staining, and Epo protein and its mRNA levels were assessed by immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR), respectively. Our results showed that after reperfusion, Epo was found to be expressed extensively in the rat brain. It was most apparent in the basal nuclei and hippocampus, and was, to some extent, present in cortex. Preconditioning with 3-NPA caused a reduction in infarct volume. The expression of both Epo protein and mRNA increased significantly in the different brain areas in the 3-NPA pretreated group as compared with the non-pretreated ischemia model group. These results suggested that preconditioning with low dose 3-NPA could induce ischemic tolerance and neuro-protective effects by increasing the Epo expression in the ischemic and ischemia-related areas.

Topics: Animals; Erythropoietin; Immunohistochemistry; Infarction, Middle Cerebral Artery; Ischemic Preconditioning; Male; Nitro Compounds; Propionates; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger