Cerebrolysin restores MPTP-induced neuroinflammation, oxidative stress, and neurotransmitters in a Parkinson's disease zebrafish model

Neuroprotective effects of Astilbin on MPTP-induced Parkinson's disease mice: Glial reaction, α-synuclein expression and oxidative stress

Effects of cerebrolysin (CBL) on prooxidant-antioxidant balance and oxidative stress (OS) developing in blood of patients with Parkinson’s disease (PD) were studied. Twenty patients with PD and 10 healthy persons (control) participated in this study. Clinical diagnosis of PD was established according UK Brain Bank Criteria; the grades of PD were II-III after Hoehn/Yahr. PD patients received therapy with CBL administration intravenously at dose 20 ml (61.5 mg/kg) per day along 10 days. As OS biomarkers, lipid peroxidation (from the formation of thiobarbituric acid – reactive substances, TBARS), H2O2 production, the activities of SOD, catalase, and GPx, as well as glutathione pool indexes were measured in blood plasma and erythrocytes. It was established a significant rise in TBARS in plasma and H2O2 contents in erythrocytes from patients with PD compared to control. These events were accompanied by an increase in the SOD and catalase activities in plasma and a decrease in GSH content and GPx activity in erythrocytes. CBL administration counteracts the TBARS accumulation, reduces hyperactivation of SOD and catalase in plasma compared with the CBL-untreated patients. In erythrocytes of PD patients, CBL injection caused the limitation of H2O2 production as well as promotion the GSH pool recovery through an increase in GSH level and GPx activity.

RIP1/RIP3/MLKL mediates dopaminergic neuron necroptosis in a mouse model of Parkinson disease

Parkinson’s disease (PD) is a debilitating neurological disorder characterized by motor dysfunction, which has been associated with alterations in the gut microbiota. Lactobacillus reuteri (L. reuteri), a safe and versatile probiotic, exhibits potent immunomodulatory functions and neuroprotective effects. However, the extent and mechanisms by which L. reuteri mitigates PD remain unclear. Here, we demonstrated that L. reuteri significantly alleviated MPTP-induced PD in mice. Importantly, we found that the protective effects of L. reuteri are mediated by its bioactive metabolites rather than the bacteria themselves. Specifically, L. reuteri elevated the levels of γ-aminobutyric acid (GABA). Administration of GABA to mice mitigated MPTP-induced PD. Mechanistically, GABA inhibited MPTP-induced ferroptosis in neuronal cells through activation of the AKT-GSK3β-GPX4 pathway via the GABA receptor. Collectively, our research elucidates that L. reuteri-derived GABA attenuates MPTP-induced PD by inhibiting ferroptosis via the AKT-GSK3β-GPX4 axis, providing a potential therapeutic approach for the prevention and treatment of PD.

Parkinson's disease is caused by damage to substantia nigra dopaminergic neurons. Factors such as oxidative stress, inflammatory factors, and acetylcholinesterase activity may induce this disease. On the other hand, crocin-one of the active ingredients of saffron-has anti-oxidant and anti-inflammatory properties. This study was performed to evaluate the protective effect of crocin to decrease dopaminergic neuron damage and Parkinson's disease complications induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A set of 24 male BALB/c Mice were divided randomly into four groups: (1) MPTP group receiving 30mg/kg MPTP for 5days; (2) MPTP + crocin group receiving 30mg/kg MPTP for 5days and 30mg/kg crocin for 15days; (3) NS group receiving normal saline for 5days; and (4) NSIG group receiving normal saline intraperitoneally for 5days and also normal saline by gavage for 15days. After the treatment period, pole and hanging motor tests were performed in all groups. Then, the brains of all the animals were removed and fixed in formalin, prepared according to routine histologic methods and cut into sections of 5µm thickness. Prepared sections were stained by immunohistochemistry techniques and toluidine blue to detect tyrosine-hydroxylase (TH)-positive neurons and dark neurons, respectively. Finally, the mean number of these cells were calculated by stereological methods and compared with the statistical tests in different groups. The results showed a significant increase in the time taken for the animal to fall from the pole in the MPTP group in comparison with other groups (P < 0.001). The time taken for them to stay on the wire in the hanging test decreased significantly in the MPTP group compared to the other groups (P < 0.001).,while in the MPTP + crocin group, the time to falling decreased (P < 0.05) and the time staying on the wire increased (P < 0.001) compared to the MPTP group. The number of TH-positive neurons in the MPTP group also decreased significantly in comparison with saline and MPTP + crocin groups (P < 0.001). The number of dark neuron sin the MPTP group increased significantly as compared with saline and the MPTP + Crocin groups (P < 0.001). Our results showed that crocin improves MPTP-induced Parkinson's disease complications and decreases cell death in the substantia nigra.

Rearing in enriched environment (EE) improves the recuperation in animal models of Parkinson's disease (PD). Administration of TiO2-nanowired cerebrolysin (CBL) could represent an additional strategy to protect or repair the nigrostriatal system. This study aims to explore morphofunctional and biochemical changes in a preclinical stage of PD testing the synergistic efficiency of combining both strategies, housing in EE, and nanodelivery of CBL. Sprague-Dawley male rats receiving intrastriatally 6-hydroxydopamine after a short evolution time were segregated into CBL group (rats receiving nanowired CBL), EE group (rats housed in EE), CBL+EE group (rats housed in EE and receiving nanowired CBL), and control group (rats without additional treatment). Prodromic stage and treatment effects were characterized by the presence of motor symptoms (amphetamine-induced rotational behavior test). Tyrosine hydroxylase (TH) immunohistochemistry and Western blot (p-Akt/Akt and p-ERK/ERK 1/2 as survival markers and caspase-3 as apoptotic marker) were performed in striatum and SN. A decrease in motor symptoms was shown by rats receiving CBL. EE monitoring cages revealed that rats from CBL+EE group showed more significant number of laps in the wheel than EE group. In SN, CBL+EE group also presented the highest neuronal density. Moreover, p-Akt/Akt and p-ERK/ERK 1/2 ratio was significant higher and caspase-3 expression was lower in CBL+EE group. In conclusion, the combination of CBL and EE provided evidence of neuoprotective-neurorestorative mechanisms by which this combined strategy promoted morphofunctional improvement by activation of survival pathways after dopamine depletion in a preclinical model of PD.

BackgroundParkinson’s disease (PD) is a prevalent neurodegenerative disease. Long noncoding RNA small molecule RNA host gene 1 (SNHG1) has been reported to play critical roles in Parkinson’s disease (PD) progression. The study aimed to further elucidate the mechanism of SNHG1 in PD pathogenesis.MethodsThe levels of SNHG1, miR-125b-5p and mitogen-activated protein kinase 1 (MAPK1) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell viability and apoptosis were evaluated by Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. The activity of Caspase-3 or Caspase-9 was measured using a Caspase-3 or Caspase-9 Assay Kit. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, lactic dehydrogenase (LDH) activity, reactive oxygen species (ROS) generation and superoxide dismutase (SOD) activity were gauged by enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter assay was performed to identify the relationship between miR-125b-5p and SNHG1 or MAPK1. The MPTP-induced PD mouse was used as an in vivo model of PD and MPP+-treated SK-N-SH and MN9D cells were used as in vitro models of PD.ResultsSNHG1 and MAPK1 were significantly up-regulated while miR-125b-5p was down-regulated in the MPTP-induced PD mouse model and MPP+-induced PD cell models. SNHG1 silence or miR-125b-5p overexpression protected against MPP+-evoked apoptosis, oxidative stress and inflammation in SK-N-SH and MN9D cells. Moreover, SNHG1 acted as a molecular sponge of miR-125b-5p, and the protective impact of SNHG1 silence on MPP+-evoked cell damage was reversed by miR-125b-5p inhibition. Furthermore, MAPK1 was a functional target of miR-125b-5p and its overexpression attenuated the effects of miR-125b-5p restoration in MPP+-triggered cell injury. In addition, the behavioral changes in MPTP-induced PD mouse in vivo model were relieved by SNHG1 silence.ConclusionSNHG1 knockdown exerted neuroprotective effects in MPP+-evoked cytotoxicity through regulating the miR-125b-5p/MAPK1 axis both in human and mouse PD cell models, highlighting a possible target for PD therapy.

Cerebrolysin attenuates ethanol-induced spatial memory impairments through inhibition of hippocampal oxidative stress and apoptotic cell death in rats.

Parkinson's disease (PD) is a disorder of neurodegeneration. Imperatorin is an active natural furocoumarin characterized by antioxidant, anti-inflammatory, and potent vasodilatory properties. Therefore, we aimed to investigate the biological functions of imperatorin and its mechanisms against PD progression. C57BL/6 mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg) daily for 5 consecutive days to mimic PD conditions in vivo. The MPTP-induced PD model mice were intraperitoneally injected with imperatorin (5 mg/kg) for 25 consecutive days after MPTP administration. The motor and cognitive functions of mice were examined by rotarod test, hanging test, narrow beam test and Morris water maze test. After analysis of MWM test, the expression levels of tyrosine hydroxylase and Iba-1 in the substantia nigra pars compacta were measured by immunohistochemistry staining, immunofluorescence staining and western blotting. The expression levels of striatal dopamine and its metabolite 3,4-dihydroxyphenylacetic acid were also measured. The protein levels of inducible nitric-oxide synthase, cyclooxygenase-2, phosphorylated phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (Akt) in the mouse striatum were estimated by western blotting. The expression levels of proinflammatory cytokines including tumor necrosis factor, interleukin (IL)-1β and IL-6 in the mouse striatum were measured by ELISA kits. The expression levels of superoxide dismutase, malondialdehyde and glutathione in the mouse midbrains were measured with commercially available kits. TUNEL staining was performed to identify the apoptosis of midbrain cells. Histopathologic changes in the mouse striata were assessed by hematoxylin-eosin staining. Imperatorin treatment markedly improved spatial learning and memory abilities of MPTP-induced PD mice. The MPTP-induced dopaminergic neuron loss in the mouse striata was inhibited by imperatorin. Imperatorin also suppressed neuroinflammation and neuronal oxidative stress in the midbrains of MPTP-induced PD mice. Mechanistically, imperatorin treatment inhibited the MPTP-induced reduction in the PI3K/Akt pathway. Imperatorin treatment can prevent dopaminergic neuron degeneration and improve cognitive functions via its potent antioxidant and anti-inflammatory properties in an MPTP-induced PD model in mice by regulating the PI3K/Akt pathway.

Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson’s disease (PD). Altered redox homeostasis in neurons interferes with several biological processes, ultimately leading to neuronal death. Oxidative damage has been identified as one of the principal mechanisms underlying the progression of PD. Several studies highlight the key role of superoxide radicals in inducing neuronal toxicity. Batryticatus Bombyx (BB), the dried larva of Bombyx mori L. infected by Beauveria bassiana (Bals.) Vuill., has been used in traditional medicine for its various pharmacological effects. In the present study, BB showed a beneficial effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity by directly targeting dopaminergic neurons. Treatment with BB improved behavioral impairments, protected dopaminergic neurons, and maintained dopamine levels in PD mouse models. Here, we investigated the protective effects of BB on MPTP-induced PD in mice and explored the underlying mechanisms of action, focusing on oxidative signaling. In MPTP-induced PD, BB promoted recovery from impaired movement, prevented dopamine depletion, and protected against dopaminergic neuronal degradation in the substantia nigra pars compacta (SNpc) or the striatum (ST). Moreover, BB upregulated mediators of antioxidative response such as superoxidase dismutase (SOD), catalase (CAT), glutathione (GSH), Heme oxygenase 1 (HO-1), and NAD(P)H (nicotinamide adenine dinucleotide phosphate) dehydrogenase (NQO1). Thus, treatment with BB reduced the oxidative stress, improved behavioral impairments, and protected against dopamine depletion in MPTP-induced toxicity.

Knockdown of long non-coding RNA AL049437 mitigates MPP+ -induced neuronal injury in SH-SY5Y cells via the microRNA-205-5p/MAPK1 axis

Cerebrolysin prevents sleep deprivation induced memory impairment and oxidative stress

1H NMR-based metabolomics study on a goldfish model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

BackgroundExosome Lnc A2M-AS1 from olfactory mucosa mesenchymal stem cells (OM-MSCs) can ameliorate oxidative stress by improving mitophagy in cardiomuscular cells; however, it remains unclear whether this effect exists in the brain tissues of patients with Parkinson’s disease (PD).MethodsOM-MSC–Exosomes were isolated and verified based on morphology and specific biomarkers. The effects of OM-MSC-Exo on mitochondrial autophagy, oxidative stress, and lncRNA A2M-AS1 were detected in MPP+-treated HT22 cells. The effects of OM-MSC-Exos on mitochondrial autophagy and oxidative stress were detected in an MPTP-induced Parkinson's disease (PD) model in C57BL/6 mice. The interaction between IGF2BP1, A2M-AS1, and TP53INP1 was assessed via RNA pull-down/RNA Immunoprecipitation and RNA stability assays. The effects of lnc A2M-AS1 on IGF2BP1/TP53INP1-mediated mitochondrial autophagy and oxidative stress were verified in MPP+-treated HT22 cells and MPTP-induced PD mouse models.ResultsExosomes isolated from olfactory mucosa mesenchymal stem cells were found to be rich in Lnc A2M-AS1. Lnc A2M-AS1 was proved to be able to ameliorate oxidative stress induced by MPP+ in HT22 cells. lncRNA A2M-AS1 regulates oxidative stress by enhancing mitophagy in HT22 cells. In addition, lncRNA A2M-AS1 induced mitophagy through TP53INP1 and mediated TP53INP1 expression by binding to IGF2BP1. Furthermore, OM-MSC-Exo and Lnc A2M-AS1 treatment improved symptoms and ameliorated oxidative stress in MPTP-induced PD mouse models.ConclusionCollectively, lncRNA A2M-AS1 from OM-MSC-derived exosomes regulates TP53INP1 expression by targeting IGF2BP1 to induce mitophagy and ameliorate oxidative stress. OM-MSC-derived exosomes could potentially serve as promising candidates for new treatment methods for PD.Graphical

Parkinson's disease (PD) ranks as the second most neurodegenerative disease characterized by loss of neurons, bradykinesia, anosmia, sleep disorder, and motor deficiency with increased global prevalence. Here, we have analyzed daidzein's neuroprotective functions in in vitro and in vivo models of PD. BV2 microglial cells induced with lipopolysaccharide (LPS) and C57BL6 mice induced with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) were used in this study to investigate neuroprotective functions of daidzein. BV2 cells induced with LPS do not exert and significant (p < 0.05) reduction in cell viability up to concentration range (5-100 µM/ml). Furthermore, LPS exposed BV2 microglia exhibited significantly (p < 0.05) increased NO production, pro-inflammatory mediators PGE2, interleukin-6 (IL6), and interleukin-1β (IL-1β) levels. Treatment with daidzein (10, 25, and 50 µM/ml) to LPS-induced BV2 microglia exhibited significantly (p < 0.05) decreased NO, pro-inflammatory mediators PGE2, IL6, and IlL-1β. Similar to the in vitro results, C57BL6 mice induced with MPTP showed defects in motor functions as observed from altered forelimb and hindlimb footprint analyses, grip strength, and perturbed motor coordination observed via rotarod tests. Additionally, levels of dopamine were significantly reduced, andpro-inflammatory mediators tumor necrosis factor alpha (TNF-α), IL-1β, IL6 were found to be increased in MPTP-induced C57BL6 PD mice. Administering daidzein significantly restored the functional levels of dopamine and pro-inflammatory mediators TNF-α, IL-1β, IL6 to near normal physiology as seen in healthy C57BL6 mice controls. Similarly, daidzein treatment to PD mice also restored the histological architecture to near normal levels as in control mice. Together, our results collectively endorse the neuroprotective functions of daidzein as observed from our initial studies, and further studies aimed at investigating daidzein's ability in regulating the catecholamine synthesis pathway to protect substantia nigra pars compacta (SNpc) neurons arein focus.