Browsing by Subject "Neuroinflammation"

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  • Lainiola, Mira; Linden, Anni-Maija (2017)
    Neuroinflammation may play an important role in the development of alcohol addiction. Recent pre-clinical reports suggest that enhanced innate immune system signaling increases consumption of alcohol. Our aim was to study whether consequences of lipopolysaccharide (LPS)-induced sickness reaction increase long-term alcohol intake. Adult male C57BL/6j mice, housed in individually ventilated cages, were injected with LPS intraperitoneally (i.p.) and allowed to recover from an acute sickness reaction for 1 week before analysis of their alcohol intake in two different drinking models. Effects of LPS challenge were tested in a continuous two-bottle free choice test with increasing concentrations of alcohol and in a drinking in the dark (DID) binge model. In addition, the effect of repeatedly administered LPS during abstinence periods between binge drinking was analyzed in the DID model. In addition, the DID model was used to study the effects of the microglia inhibitor minocycline (50 mg/kg/day, 4 days) and purinergic P2X7 receptor antagonist Brilliant Blue G (75 mg/kg/day, 7 days) on alcohol intake. In contrast to previous findings, pretreatment with a 1-mg/kg dose of LPS did not significantly increase ethanol consumption in the continuous two-bottle choice test. As a novel finding, we report that increasing the LPS dose to 1.5 mg/kg reduced consumption of 18 and 21% (v/v) ethanol. In the DID model, pretreatment with LPS (0.2-1.5 mg/kg) did not significantly alter 15% or 20% ethanol consumption. Neither did repeated LPS injections affect binge alcohol drinking. Minocycline reduced alcohol, but also water, intake regardless of LPS pretreatment. No data on effects of P2X7 antagonists on alcohol consumption have been previously published; therefore, we report here that subchronic Brilliant Blue G had no effect on alcohol intake in the DID model. As a conclusion, further studies are needed to validate this LPS model of the interaction between immune system activation and alcohol consumption. (C) 2017 Elsevier Inc. All rights reserved.
  • Lindholm, Dan; Mäkelä, Johanna; Di Liberto, Valentina; Mudo, Giuseppa; Belluardo, Natale; Eriksson-Rosenberg, Ove; Saarma, Mart (2016)
    Parkinson's disease (PD is a progressive neurological disorder characterized by the degeneration and death of midbrain dopamine and non-dopamine neurons in the brain leading to motor dysfunctions and other symptoms, which seriously influence the quality of life of PD patients. The drug L-dopa can alleviate the motor symptoms in PD, but so far there are no rational therapies targeting the underlying neurodegenerative processes. Despite intensive research, the molecular mechanisms causing neuronal loss are not fully understood which has hampered the development of new drugs and disease-modifying therapies. Neurotrophic factors are by virtue of their survival promoting activities attract candidates to counteract and possibly halt cell degeneration in PD. In particular, studies employing glial cell line-derived neurotrophic factor (GDNF) and its family member neurturin (NRTN), as well as the recently described cerebral dopamine neurotrophic factor (CDNF) and the mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown positive results in protecting and repairing dopaminergic neurons in various models of PD. Other substances with trophic actions in dopaminergic neurons include neuropeptides and small compounds that target different pathways impaired in PD, such as increased cell stress, protein handling defects, dysfunctional mitochondria and neuroinflammation. In this review, we will highlight the recent developments in this field with a focus on trophic factors and substances having the potential to beneficially influence the viability and functions of dopaminergic neurons as shown in preclinical or in animal models of PD.
  • Martiskainen, Henna; Paldanius, Kaisa M A; Natunen, Teemu; Takalo, Mari; Marttinen, Mikael; Leskelä, Stina; Huber, Nadine; Mäkinen, Petra; Bertling, Enni; Dhungana, Hiramani; Huuskonen, Mikko; Honkakoski, Paavo; Hotulainen, Pirta; Rilla, Kirsi; Koistinaho, Jari; Soininen, Hilkka; Malm, Tarja; Haapasalo, Annakaisa; Hiltunen, Mikko (BioMed Central, 2017)
    Abstract Background DHCR24, involved in the de novo synthesis of cholesterol and protection of neuronal cells against different stress conditions, has been shown to be selectively downregulated in neurons of the affected brain areas in Alzheimer’s disease. Methods Here, we investigated whether the overexpression of DHCR24 protects neurons against inflammation-induced neuronal death using co-cultures of mouse embryonic primary cortical neurons and BV2 microglial cells upon acute neuroinflammation. Moreover, the effects of DHCR24 overexpression on dendritic spine density and morphology in cultured mature mouse hippocampal neurons and on the outcome measures of ischemia-induced brain damage in vivo in mice were assessed. Results Overexpression of DHCR24 reduced the loss of neurons under inflammation elicited by LPS and IFN-γ treatment in co-cultures of mouse neurons and BV2 microglial cells but did not affect the production of neuroinflammatory mediators, total cellular cholesterol levels, or the activity of proteins linked with neuroprotective signaling. Conversely, the levels of post-synaptic cell adhesion protein neuroligin-1 were significantly increased upon the overexpression of DHCR24 in basal growth conditions. Augmentation of DHCR24 also increased the total number of dendritic spines and the proportion of mushroom spines in mature mouse hippocampal neurons. In vivo, overexpression of DHCR24 in striatum reduced the lesion size measured by MRI in a mouse model of transient focal ischemia. Conclusions These results suggest that the augmentation of DHCR24 levels provides neuroprotection in acute stress conditions, which lead to neuronal loss in vitro and in vivo.
  • Loppi, S.; Kolosowska, N.; Kärkkäinen, O.; Korhonen, P.; Huuskonen, M.; Grubman, A.; Dhungana, H.; Wojciechowski, S.; Pomeshchik, Y.; Giordano, M.; Kagechika, H.; White, A.; Auriola, S.; Koistinaho, J.; Landreth, G.; Hanhineva, K.; Kanninen, K.; Malm, T. (2018)
    Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.
  • Chaudhry, Shafqat R.; Lendvai, Ilana S.; Muhammad, Sajjad; Westhofen, Philipp; Kruppenbacher, Johannes; Scheef, Lukas; Boecker, Henning; Scheele, Dirk; Hurlemann, Rene; Kinfe, Thomas M. (2019)
    Objective: To assay peripheral inter-ictal cytokine serum levels and possible relations with non-invasive vagus nerve stimulation (nVNS) responsiveness in migraineurs. Methods: This double-blinded, sham-controlled study enrolled 48 subjects and measured headache severity, frequency [headache days/month, number of total and mild/moderate/severe classified attacks/month], functional state [sleep, mood, body weight, migraine-associated disability] and serum levels of inflammatory markers [inter-ictal] using enzyme-linked immunoassays at baseline and after 2 months of adjunctive nVNS compared to sham stimulation and suitably matched controls. Results: No significant differences were observed at baseline and after 2 months for headache severity, total attacks/month, headache days/month and functional outcome [sleep, mood, disability] between verum and sham nVNS. However, the number of severe attacks/month significantly decreased in the verum nVNS group and circulating pro-inflammatory IL-1 beta was elevated significantly in the sham group compared to nVNS. Levels of anti-inflammatory IL-10 were significantly higher at baseline in both groups compared to healthy controls, but not at 2 months follow-up [p <0.05]. Concentrations of high-mobility group box-1 (HMGB-1), IL-6, tumor-necrosis factor-alpha (TNF-alpha), leptin, adiponectin, ghrelin remained unchanged [p > 0.05]. No severe device-/stimulation-related adverse events occurred. Conclusion: 2 months of adjunctive cervical nVNS significantly declined the number of severe attacks/month. Pro-inflammatory IL-1 beta plasma levels [inter-ictal] were higher in sham-treated migraine patients compared to verum nVNS. However, pro- [IL-6, HMGB-1, TNF-alpha, leptin] and anti-inflammatory [IL-10, adiponectin, ghrelin] mediators did not differ statistically. Profiling of neuroinflammatory circuits in migraine to predict nVNS responsiveness remains an experimental approach, which may be biased by pre-analytic variables warranting large-scale biobank-based systematic investigations [omics]. (C) 2019 Elsevier Inc. All rights reserved.
  • Kolosowska, Natalia; Gotkiewicz, Maria; Dhungana, Hiramani; Giudice, Luca; Giugno, Rosalba; Box, Daphne; Huuskonen, Mikko T.; Korhonen, Paula; Scoyni, Flavia; Kanninen, Katja M.; Yla-Herttuala, Seppo; Turunen, Tiia A.; Turunen, Mikko P.; Koistinaho, Jari; Malm, Tarja (2020)
    Background Ischemic stroke is a devastating disease without a cure. The available treatments for ischemic stroke, thrombolysis by tissue plasminogen activator, and thrombectomy are suitable only to a fraction of patients and thus novel therapeutic approaches are urgently needed. The neuroinflammatory responses elicited secondary to the ischemic attack further aggravate the stroke-induced neuronal damage. It has been demonstrated that these responses are regulated at the level of non-coding RNAs, especially miRNAs. Methods We utilized lentiviral vectors to overexpress miR-669c in BV2 microglial cells in order to modulate their polarization. To detect whether the modulation of microglial activation by miR-669c provides protection in a mouse model of transient focal ischemic stroke, miR-669c overexpression was driven by a lentiviral vector injected into the striatum prior to induction of ischemic stroke. Results Here, we demonstrate that miR-669c-3p, a member of chromosome 2 miRNA cluster (C2MC), is induced upon hypoxic and excitotoxic conditions in vitro and in two different in vivo models of stroke. Rather than directly regulating the neuronal survival in vitro, miR-669c is capable of attenuating the microglial proinflammatory activation in vitro and inducing the expression of microglial alternative activation markers arginase 1 (Arg1), chitinase-like 3 (Ym1), and peroxisome proliferator-activated receptor gamma (PPAR-gamma). Intracerebral overexpression of miR-669c significantly decreased the ischemia-induced cell death and ameliorated the stroke-induced neurological deficits both at 1 and 3 days post injury (dpi). Albeit miR-669c overexpression failed to alter the overall Iba1 protein immunoreactivity, it significantly elevated Arg1 levels in the ischemic brain and increased colocalization of Arg1 and Iba1. Moreover, miR-669c overexpression under cerebral ischemia influenced several morphological characteristics of Iba1 positive cells. We further demonstrate the myeloid differentiation primary response gene 88 (MyD88) transcript as a direct target for miR-669c-3p in vitro and show reduced levels of MyD88 in miR-669c overexpressing ischemic brains in vivo. Conclusions Collectively, our data provide the evidence that miR-669c-3p is protective in a mouse model of ischemic stroke through enhancement of the alternative microglial/macrophage activation and inhibition of MyD88 signaling. Our results accentuate the importance of controlling miRNA-regulated responses for the therapeutic benefit in conditions of stroke and neuroinflammation.
  • Kolosowska, Natalia; Gotkiewicz, Maria; Dhungana, Hiramani; Giudice, Luca; Giugno, Rosalba; Box, Daphne; Huuskonen, Mikko T; Korhonen, Paula; Scoyni, Flavia; Kanninen, Katja M; Ylä-Herttuala, Seppo; Turunen, Tiia A; Turunen, Mikko P; Koistinaho, Jari; Malm, Tarja (BioMed Central, 2020)
    Abstract Background Ischemic stroke is a devastating disease without a cure. The available treatments for ischemic stroke, thrombolysis by tissue plasminogen activator, and thrombectomy are suitable only to a fraction of patients and thus novel therapeutic approaches are urgently needed. The neuroinflammatory responses elicited secondary to the ischemic attack further aggravate the stroke-induced neuronal damage. It has been demonstrated that these responses are regulated at the level of non-coding RNAs, especially miRNAs. Methods We utilized lentiviral vectors to overexpress miR-669c in BV2 microglial cells in order to modulate their polarization. To detect whether the modulation of microglial activation by miR-669c provides protection in a mouse model of transient focal ischemic stroke, miR-669c overexpression was driven by a lentiviral vector injected into the striatum prior to induction of ischemic stroke. Results Here, we demonstrate that miR-669c-3p, a member of chromosome 2 miRNA cluster (C2MC), is induced upon hypoxic and excitotoxic conditions in vitro and in two different in vivo models of stroke. Rather than directly regulating the neuronal survival in vitro, miR-669c is capable of attenuating the microglial proinflammatory activation in vitro and inducing the expression of microglial alternative activation markers arginase 1 (Arg1), chitinase-like 3 (Ym1), and peroxisome proliferator-activated receptor gamma (PPAR-γ). Intracerebral overexpression of miR-669c significantly decreased the ischemia-induced cell death and ameliorated the stroke-induced neurological deficits both at 1 and 3 days post injury (dpi). Albeit miR-669c overexpression failed to alter the overall Iba1 protein immunoreactivity, it significantly elevated Arg1 levels in the ischemic brain and increased colocalization of Arg1 and Iba1. Moreover, miR-669c overexpression under cerebral ischemia influenced several morphological characteristics of Iba1 positive cells. We further demonstrate the myeloid differentiation primary response gene 88 (MyD88) transcript as a direct target for miR-669c-3p in vitro and show reduced levels of MyD88 in miR-669c overexpressing ischemic brains in vivo. Conclusions Collectively, our data provide the evidence that miR-669c-3p is protective in a mouse model of ischemic stroke through enhancement of the alternative microglial/macrophage activation and inhibition of MyD88 signaling. Our results accentuate the importance of controlling miRNA-regulated responses for the therapeutic benefit in conditions of stroke and neuroinflammation.
  • Dukay, Brigitta; Walter, Fruzsina R; Vigh, Judit P; Barabási, Beáta; Hajdu, Petra; Balassa, Tamás; Migh, Ede; Kincses, András; Hoyk, Zsófia; Szögi, Titanilla; Borbély, Emőke; Csoboz, Bálint; Horváth, Péter; Fülöp, Lívia; Penke, Botond; Vígh, László; Deli, Mária A; Sántha, Miklós; Tóth, Melinda E (BioMed Central, 2021)
    Abstract Background Heat-shock protein B1 (HSPB1) is among the most well-known and versatile member of the evolutionarily conserved family of small heat-shock proteins. It has been implicated to serve a neuroprotective role against various neurological disorders via its modulatory activity on inflammation, yet its exact role in neuroinflammation is poorly understood. In order to shed light on the exact mechanism of inflammation modulation by HSPB1, we investigated the effect of HSPB1 on neuroinflammatory processes in an in vivo and in vitro model of acute brain injury. Methods In this study, we used a transgenic mouse strain overexpressing the human HSPB1 protein. In the in vivo experiments, 7-day-old transgenic and wild-type mice were treated with ethanol. Apoptotic cells were detected using TUNEL assay. The mRNA and protein levels of cytokines and glial cell markers were examined using RT-PCR and immunohistochemistry in the brain. We also established primary neuronal, astrocyte, and microglial cultures which were subjected to cytokine and ethanol treatments. TNFα and hHSPB1 levels were measured from the supernates by ELISA, and intracellular hHSPB1 expression was analyzed using fluorescent immunohistochemistry. Results Following ethanol treatment, the brains of hHSPB1-overexpressing mice showed a significantly higher mRNA level of pro-inflammatory cytokines (Tnf, Il1b), microglia (Cd68, Arg1), and astrocyte (Gfap) markers compared to wild-type brains. Microglial activation, and 1 week later, reactive astrogliosis was higher in certain brain areas of ethanol-treated transgenic mice compared to those of wild-types. Despite the remarkably high expression of pro-apoptotic Tnf, hHSPB1-overexpressing mice did not exhibit higher level of apoptosis. Our data suggest that intracellular hHSPB1, showing the highest level in primary astrocytes, was responsible for the inflammation-regulating effects. Microglia cells were the main source of TNFα in our model. Microglia isolated from hHSPB1-overexpressing mice showed a significantly higher release of TNFα compared to wild-type cells under inflammatory conditions. Conclusions Our work provides novel in vivo evidence that hHSPB1 overexpression has a regulating effect on acute neuroinflammation by intensifying the expression of pro-inflammatory cytokines and enhancing glial cell activation, but not increasing neuronal apoptosis. These results suggest that hHSPB1 may play a complex role in the modulation of the ethanol-induced neuroinflammatory response.
  • Savolainen, Mari H.; Albert, Katrina; Airavaara, Mikko; Myohänen, Timo T. (2017)
    Proteinaceous inclusions, called Lewy bodies, are used as a pathological hallmark for Parkinson's disease (PD). Lewy bodies contain insoluble alpha-synuclein (aSyn) and many other ubiquitinated proteins, suggesting a role for protein degradation system failure in the PD pathogenesis. Indeed, proteasomal dysfunction has been linked to PD but commonly used in vivo toxin models, such as 6-OHDA or MPTP, do not have a significant effect on the proteasomal system or protein aggregation. Therefore, we wanted to study the characteristics of a proteasomal inhibitor, lactacystin, as a PD model on young and adult mice. To study this, we performed stereotactic microinjection of lactacystin above the substantia nigra pars compacta in young (2 month old) and adult (12-14 month old) C57Bl/6 mice. Motor behavior was measured by locomotor activity and cylinder tests, and the markers of neuroinflammation, aSyn, and dopaminergic system were assessed by immunohistochemistry and HPLC. We found that lactacystin induced a Parkinson's disease-like motor phenotype 5-7 days after injection in young and adult mice, and this was associated with widespread neuroinflammation based on glial cell markers, aSyn accumulation in substantia nigra, striatal dopamine decrease, and loss of dopaminergic cell bodies in the substantia nigra and terminals in the striatum. When comparing young and adult mice, adult mice were more sensitive for dopaminergic degeneration after lactacystin injection that further supports the use of adult mice instead of young when modeling neurodegeneration. Our data showed that lactacystin is useful in modeling various aspects of Parkinson's disease, and taken together, our findings emphasize the role of a protein degradation deficit in Parkinson's disease pathology, and support the use of proteasomal inhibitors as Parkinson's disease models.
  • Sarajärvi, T.; Jäntti, M.; Paldanius, K. M. A.; Natunen, T.; Wu, J. C.; Mäkinen, P.; Tarvainen, I.; Tuominen, R. K.; Talman, V.; Hiltunen, M. (2018)
    Abnormal protein kinase C (PKC) function contributes to many pathophysiological processes relevant for Alzheimer's disease (AD), such as amyloid precursor protein (APP) processing. Phorbol esters and other PKC activators have been demonstrated to enhance the secretion of soluble APP alpha (sAPP alpha), reduce the levels of beta-amyloid (A beta), induce synaptogenesis, and promote neuroprotection. We have previously described isophthalate derivatives as a structurally simple family of PKC activators. Here, we characterised the effects of isophthalate derivatives HMI-1a3 and HMI-1b11 on neuronal viability, neuroinflammatory response, processing of APP and dendritic spine density and morphology in in vitro. HMI-1a3 increased the viability of embryonic primary cortical neurons and decreased the production of the pro-inflammatory mediator TNF alpha, but not that of nitric oxide, in mouse neuron-BV2 microglia co-cultures upon LPS- and IFN-gamma-induced neuroinflammation. Furthermore, both HMI-1a3 and HMI-1b11 increased the levels of sAPPa relative to total sAPP and the ratio of A beta 42/A beta 40 in human SH-Sv5v neuroblastoma cells. Finally, bryostatin-1, but not HMI-1a3, increased the number of mushroom spines in proportion to total spine density in mature mouse hippocampal neuron cultures. These results suggest that the PKC activator HMI-1a3 exerts neuroprotective functions in the in vitro models relevant for AD by reducing the production of TNF alpha and increasing the secretion of neuroprotective sAPPa.