Neurochemistry

Interleukin-1 receptor antagonist ameliorates the pain hypersensitivity, spinal inflammation and oxidative stress induced by systemic lipopolysaccharide in neonatal rats Publication date: May 2020 Source: Neurochemistry International, Volume 135 Author(s): Cheng-Ta Hsieh, Yih-Jing Lee, Jonathan W. Lee, Silu Lu, Michelle A. Tucci, Xiaoli Dai, Norma Beatriz Ojeda, Hyun Joon Lee, Lir-Wan Fan, Lu-Tai Tien Abstract Perinatal inflammation-induced reduction in pain threshold may alter pain sensitivity to hyperalgesia or allodynia which may persist into adulthood. In this study, we investigated the anti-inflammatory protective effect of interleukin-1 receptor antagonist (IL-1ra), an anti-inflammatory cytokine, on systemic lipopolysaccharide (LPS)-induced spinal cord inflammation and oxidative stress, thermal hyperalgesia, and mechanical allodynia in neonatal rats. Intraperitoneal (i.p.) injection of LPS (2 mg/kg) or sterile saline was performed in postnatal day 5 (P5) rat pups, and IL-1ra (100 mg/kg) or saline was administered (i.p.) 5 min after LPS injection. Pain reflex behavior, spinal cord inflammation and oxidative stress were examined 24 h after LPS administration. Systemic LPS exposure led to a reduction of tactile threshold in the von Frey filament tests (mechanical allodynia) and pain response latency in the tail-flick test (thermal hyperalgesia) of P6 neonatal rats. Spinal cord inflammation was indicated by the increased numbers of activated glial cells including microglia (Iba1+) and astrocytes (GFAP+), and elevated levels of pro-inflammatory cytokine interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) 24 h after LPS treatment. LPS treatment induced spinal oxidative stress as evidenced by the increase in thiobarbituric acid reactive substances (TBARS) content in the spinal cord. LPS exposure also led to a significant increase in oligodendrocyte lineage population (Olig2+) and mature oligodendrocyte cells (APC+) in the neonatal rat spinal cord. IL-1ra treatment significantly reduced LPS-induced effects including hyperalgesia, allodynia, the increased number of activated microglia, astrocytes and oligodendrocytes, and elevated levels of IL-1β, COX-2, PGE2, and lipid peroxidation (TBARS) in the neonatal rat spinal cord. These data suggest that IL-1ra provides a protective effect against the development of pain hypersensitivity, spinal cord inflammation and oxidative stress in the neonatal rats following LPS exposure, which may be associated with the blockade of LPS-induced pro-inflammatory cytokine IL-1β.

Remote ischemic conditioning reduced cerebral ischemic injury by modulating inflammatory responses and ERK activity in type 2 diabetic mice Publication date: May 2020 Source: Neurochemistry International, Volume 135 Author(s): Cuiying Liu, Jian Yang, Chencheng Zhang, Xiaokun Geng, Heng Zhao Abstract Remote ischemic preconditioning (RIPreC) and postconditioning (RIPostC) have been demonstrated to attenuate brain injury after ischemic stroke in healthy animals. This study investigated whether RIPreC and RIPostC exerted neuroprotection against cerebral ischemic injury in type 2 diabetic mice. RIPreC (24 h before ischemia) and RIPostC (immediately after reperfusion) were performed in an ischemia/reperfusion induced stroke model with type 2 diabetes. Ischemic outcomes, flow cytometry, multiplex cytokine assay, and western blotting were analyzed after 45 min of ischemia followed by 48 h of reperfusion. Our data indicated that RIPreC and RIPostC attenuated cerebral injuries and neurological deficits. RIPreC significantly reduced CD4 T cell and CD8 T cell infiltration and increased B cell infiltration into the ischemic brain. It also upregulated CD4 and CD8 T cell levels in the peripheral blood. However, RIPostC significantly decreased CD8 T cells infiltration and increased B cell infiltration into the ischemic brain. RIPreC inhibited IL-6 level in both the brain and blood, while RIPostC treatment attenuated IL-6 level upregulation in the peripheral blood. In addition, both RIPreC and RIPostC significantly increased p-ERK expression in the ipsilateral hemisphere in diabetic mice. This study indicated that RIPreC and RIPostC neuroprotection is present in type 2 diabetic mice via the modulation of brain ERK activity and inflammatory responses in both the peripheral blood and ischemic brain. However, the benefit was lower in RIPostC.

The effects of manganese overexposure on brain health Publication date: May 2020 Source: Neurochemistry International, Volume 135 Author(s): Mahfuzur R. Miah, Omamuyovwi M. Ijomone, Comfort O.A. Okoh, Olayemi K. Ijomone, Grace T. Akingbade, Tao Ke, Bárbara Krum, Airton da Cunha Martins, Ayodele Akinyemi, Nicole Aranoff, Felix Alexandre Antunes Soares, Aaron B. Bowman, Michael Aschner Abstract Manganese (Mn) is the twelfth most abundant element on the earth and an essential metal to human health. Mn is present at low concentrations in a variety of dietary sources, which provides adequate Mn content to sustain support various physiological processes in the human body. However, with the rise of Mn utility in a variety of industries, there is an increased risk of overexposure to this transition metal, which can have neurotoxic consequences. This risk includes occupational exposure of Mn to workers as well as overall increased Mn pollution affecting the general public. Here, we review exposure due to air pollution and inhalation in industrial settings; we also delve into the toxic effects of manganese on the brain such as oxidative stress, inflammatory response and transporter dysregulation. Additionally, we summarize current understandings underlying the mechanisms of Mn toxicity.

Treadmill exercise restores memory and hippocampal synaptic plasticity impairments in ovalbumin-sensitized juvenile rats: Involvement of brain-derived neurotrophic factor (BDNF) Publication date: May 2020 Source: Neurochemistry International, Volume 135 Author(s): Amin Mokhtari-Zaer, Saeideh Saadat, Narges Marefati, Mahmoud Hosseini, Mohammad Hossein Boskabady Abstract Studies demonstrate that asthma, especially during childhood, affects the functions of the brain including learning and memory. Exercise is well known for its neuroprotective functions and for its beneficial effects on asthma. We aimed to assess the effects of exercise on cognitive function, synaptic plasticity, and hippocampal brain-derived neurotrophic factor (BDNF) levels in ovalbumin (OVA) sensitized juvenile rats. Rats were sensitized by intraperitoneal administration and inhaled OVA. Animals were subjected to treadmill running exercise during the OVA-challenged period. T-helper type 2 (Th2) cytokine [interleukin (IL)-4], Th1 cytokine (INF-γ) levels, and INF-γ/IL-4 (Th1/Th2) ratio in bronchoalveolar lavage fluid (BALF), and tracheal response to methacholine and OVA were measured. Further, memory behaviors and BDNF levels were measured in the hippocampus as well as long-term potentiation (LTP) was assessed by recording field excitatory postsynaptic potentials (fEPSPs) in the hippocampus. The levels of IL-4 and TGF-β were decreased but INF-γ level and INF-γ/IL-4 ratio increased in the BALF due to exercise in the OVA-sensitized animals. In addition, exercise improved OVA-sensitization induced cognitive impairments, increased BDNF levels, and enhanced hippocampal LTP in OVA-sensitized rats. Exercise is not only effective in the alleviation of airway inflammation by restoring Th1/Th2 cytokines balance, but also is a candidate for improvement of memory and synaptic plasticity deficits partially through increasing the levels of hippocampal BDNF in OVA-sensitized rats.

Fluoxetine improves behavioural deficits induced by chronic alcohol treatment by alleviating RNA editing of 5-HT2C receptors Publication date: March 2020 Source: Neurochemistry International, Volume 134 Author(s): Zexiong Li, Yan Lu, Shanshan Liang, Shuai Li, Beina Chen, Manman Zhang, Maosheng Xia, Dawei Guan, Alexei Verkhratsky, Baoman Li Abstract The alcoholism and major depressive disorder are common comorbidity, with alcohol-induced depressive symptoms being eased by selective serotonin re-uptake inhibitors (SSRIs), although the mechanisms underlying pathology and therapy are poorly understood. Chronic alcohol consumption affects the activity of serotonin 2C receptors (5-HT2CR) by regulating adenosine deaminases acting on RNA (ADARs) in neurons. Astrogliopathic changes contribute to alcohol addiction, while decreased release of ATP from astrocytes can trigger depressive-like behaviours in mice. In this study, we discovered that chronic alcohol treatment increased editing of RNA of 5-HT2CR via up-regulating the expression of ADAR2, consequently reducing the release of ATP from astrocytes induced by 5-HT2CR agonist, MK212. Moreover, SSRI antidepressant fluoxetine decreased the expression of ADAR2 through the transactivation of EGFR/PI3K/AKT/cFos signalling pathway. The increased release of astroglial ATP by MK212 which was suppressed by chronic alcohol consumption, and reduction in ADAR2 activity eliminated the RNA editing of 5-HT2CR increased by alcohol in vitro and recovered the release of ATP from astrocytes induced by MK212. Meanwhile, fluoxetine improved the behavioural and motor symptoms induced by alcohol addiction and decreased the alcohol intake. Our study suggests that the astrocytic 5-HT2CR contribute to alcohol addiction; fluoxetine thus can be used to alleviate depression, treat alcohol addiction and improve motor coordination. Graphical abstract

Preclinical testing of the ketogenic diet in fragile X mice Publication date: March 2020 Source: Neurochemistry International, Volume 134 Author(s): Pamela R. Westmark, Alejandra Gutierrez, Aaron K. Gholston, Taralyn M. Wilmer, Cara J. Westmark Abstract The ketogenic diet is highly effective at attenuating seizures in refractory epilepsy, and accumulating evidence in the literature suggests that it may be beneficial in autism. To our knowledge, no one has studied the ketogenic diet in any fragile X syndrome (FXS) model. FXS is the leading known genetic cause of autism. Herein, we tested the effects of chronic ketogenic diet treatment on seizures, body weight, ketone and glucose levels, diurnal activity levels, learning and memory, and anxiety behaviors in Fmr1KO and littermate control mice as a function of age. The ketogenic diet selectively attenuates seizures in male but not female Fmr1KO mice and differentially affects weight gain and diurnal activity levels dependent on Fmr1 genotype, sex and age. Graphical abstract

Involvement of TRPV1 and the efficacy of α-spinasterol on experimental fibromyalgia symptoms in mice Publication date: March 2020 Source: Neurochemistry International, Volume 134 Author(s): Susana Paula Moreira Fischer, Indiara Brusco, Evelyne Silva Brum, Maria Fernanda Pessano Fialho, Camila Camponogara, Rahisa Scussel, Ricardo Andrez Machado-de-Ávila, Gabriela Trevisan, Sara Marchesan Oliveira Abstract Fibromyalgia is characterised mainly by symptoms of chronic widespread pain and comorbidities like depression. Although these symptoms cause a notable impact on the patient's quality of life, the underlying aetiology and pathophysiology of this disease remain incompletely elucidated. The transient receptor potential vanilloid type 1 (TRPV1) is a polymodal receptor that is involved in the development of nociceptive and depressive behaviours, while α-spinasterol, a multitarget TRPV1 antagonist and cyclooxygenase inhibitor, presents antinociceptive and antidepressant effects. The present study investigated the involvement of the TRPV1 channel and the possible effects of α-spinasterol on nociceptive and depressive-like behaviours in an experimental fibromyalgia model. The fibromyalgia model was induced with a subcutaneous (s.c.) injection of reserpine (1 mg/kg) once daily for 3 consecutive days in male Swiss mice. Reserpine administration depleted monoamines and caused mechanical allodynia. This dysfunction was inhibited by SB-366791 (1 mg/kg, oral route [p.o.]), a selective TRPV1 antagonist, with a maximum inhibition (Imax) of 73.4 ± 15.5%, or by the single or 3-day-repeated administration of α-spinasterol (0.3 mg/kg, p.o.), with an Imax of 72.8 ± 17.8% and 78.9 ± 32.9%, respectively. SB-366791 also inhibited the increase of the reserpine-induced immobility time, with an Imax of 100%, while α-spinasterol inhibited this parameter with an Imax of 98.2 ± 21.5% and 100%, by single or repeated administration, respectively. The reserpine-induced mechanical allodynia and the thermal hyperalgesia were abolished by TRPV1-positive fibers desensitization induced by previous resiniferatoxin (RTX) administration. In summary, the TRPV1 channel is involved in the development and maintenance of nociception and depressive-like behaviours in a fibromyalgia model, while the α-spinasterol has therapeutic potential to treat the pain and depression symptoms in fibromyalgia patients. Graphical abstract

Polydatin protects SH-SY5Y in models of Parkinson's disease by promoting Atg5-mediated but parkin-independent autophagy Publication date: March 2020 Source: Neurochemistry International, Volume 134 Author(s): Hua Bai, Yaqi Ding, Xin Li, Deqin Kong, Chenqi Xin, Xuekang Yang, Chengwu Zhang, Ziqiang Rong, Chuanhao Yao, Shenci Lu, Lei Ji, Lin Li, Wei Huang Abstract Parkinson's disease (PD), the second most common chronic neurodegenerative disorder, broadly remains incurable. Both genetic susceptibility and exposure to deleterious environmental stimuli contribute to dopaminergic neuron degeneration in the substantia nigra. Hence, reagents that can ameliorate the phenotypes rendered by genetic or environmental factors should be considered in PD therapy. In this study, we found that polydatin (Pol), a natural compound extracted from grapes and red wines, significantly attenuated rotenone- (Rot) or Parkin deficiency-induced mitochondrial dysfunction and cell death in SH-SY5Y, a human dopaminergic neuronal cell line. We showed that Pol significantly attenuated the Rot-induced decrease in cell viability, mitochondrial membrane potential (MMP), and Sirt 1 expression and increase in cell death, reactive oxygen species (ROS) and DJ1 expression. Rot resulted in a decrease in mTOR/Ulk-involved autophagy and an increase in PGC1β/mfn2-involved mitochondrial fusion, which was inhibited by Pol. We further demonstrated that the protective effects of Pol are partially blocked when autophagy-related gene 5 (Atg5) is genetically inactivated, suggesting that Pol-mediated neuroprotection requires Atg5. Moreover, Pol rescued Parkin knockdown-induced oxidative stress, mitochondrial dysfunction, autophagy impairment, and mitochondrial fusion enhancement. Interestingly, Pol treatment could also rescue the mitochondrial morphological abnormality and motorial dysfunction of a Drosophila PD model induced by Parkin deficiency. Thus, Pol could represent a useful therapeutic strategy as a disease-modifier in PD by decreasing oxidative stress and regulating autophagic processes and mitochondrial fusion. Graphical abstract Schematic diagram underlying the protective effects of polydatin against Parkinson's disease models induced by Rot or Parkin knockdown through recovering redox balance, rescuing autophagy and inhibiting mitochondrial fusion.

Chronic constriction injury of the sciatic nerve in rats causes different activation modes of microglia between the anterior and posterior horns of the spinal cord Publication date: March 2020 Source: Neurochemistry International, Volume 134 Author(s): Tasuku Nishihara, Junya Tanaka, Keisuke Sekiya, Yuki Nishikawa, Naoki Abe, Taisuke Hamada, Sakiko Kitamura, Keizo Ikemune, Shinichiro Ochi, Mohammed E. Choudhury, Hajime Yano, Toshihiro Yorozuya Abstract Chronic constriction injury of the sciatic nerve is frequently considered as a cause of chronic neuropathic pain. Marked activation of microglia in the posterior horn (PH) has been well established with regard to this pain. However, microglial activation in the anterior horn (AH) is also strongly induced in this process. Therefore, in this study, we compared the differential activation modes of microglia in the AH and PH of the lumbar cord 7 days after chronic constriction injury of the left sciatic nerve in Wistar rats. Microglia in both the ipsilateral AH and PH demonstrated increased immunoreactivity of the microglial markers Iba1 and CD11b. Moreover, abundant CD68+ phagosomes were observed in the cytoplasm. Microglia in the AH displayed elongated somata with tightly surrounding motoneurons, whereas cells in the PH displayed a rather ameboid morphology and were attached to myelin sheaths rather than to neurons. Microglia in the AH strongly expressed NG2 chondroitin sulfate proteoglycan. Despite the tight attachment to neurons in the AH, a reduction in synaptic proteins was not evident, suggesting engagement of the activated microglia in synaptic stripping. Myelin basic protein immunoreactivity was observed in the phagosomes of activated microglia in the PH, suggesting the phagocytic removal of myelin. CCI caused both motor deficit and hyperalgesia that were evaluated by applying BBB locomotor rating scale and von Frey test, respectively. Motor defict was the most evident at postoperative day1, and that became less significant thereafter. By contrast, hyperalgesia was not severe at day 1 but it became worse at least by day 7. Collectively, the activation modes of microglia were different between the AH and PH, which may be associated with the difference in the course of motor and sensory symptoms.

Iron overload induced by IRP2 gene knockout aggravates symptoms of Parkinson's disease Publication date: March 2020 Source: Neurochemistry International, Volume 134 Author(s): Yun-Zhe Ci, Haiyan Li, Lin-Hao You, Yu Jin, Rui Zhou, Guofen Gao, Maggie Pui Man Hoi, Chunyan Wang, Yan-Zhong Chang, Peng Yu Abstract Parkinson's disease (PD) is accompanied by iron overload in the brain. However, whether iron accumulation is the cause or effect of PD is still unknown. Iron regulatory protein 2 (IRP2) plays a critical role in keeping iron homeostasis, and our previous data showed that the deletion of the IRP2 gene caused iron deposits in organs of mice. Therefore, we further investigated the role of iron overload induced by IRP2 gene deletion in the development of the MPTP-induced PD mouse model in vivo, and the underlying regulatory mechanisms in primary cultures of astrocytes in vitro. Data from neurobehavioral, immunohistochemistry, TUNEL and Elisa studies showed that MPTP treatment enhanced the symptoms of PD in vivo, increased cell apoptosis and decreased dopamine levels in IRP2−/− mice. In addition, the expression of L-ferritin and iron contents increased significantly in the substantia nigra (SN) of IRP2−/− mice. Moreover, MPTP treatment significantly increased the expression of DMT1 (-IRE) and decreased the expression of TfR1 in IRP2−/− mice. Further investigations with primary cultures of astrocytes from IRP2−/− mice showed that MPP+ increased the expression of L-ferritin and DMT1 (-IRE), and decreased the expression of TfR1. Our results demonstrated that IRP2 gene deletion induced iron accumulation in the SN, which exacerbated the neuronal apoptosis and Parkinsonism symptoms. At the same time, IRP2 gene deletion increased the iron contents in astrocytes around neurons, which further decreased their protection for neurons and increased the cell apoptosis, ultimately forming a vicious cycle that leads to the onset and progression of PD.