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Effect of manganese on neuroinflammation

}}} ---- || {{attachment:cellular_transport.png|Cilia|width="470 height=470"}} <
><>'''[[#figure_1|Fig 1.]]'''<
>''Manganese transport mechanisms'' <
>''(based on image from [[#Harischandrafig|Harischandra et al, (2019)]]'' || ~-[[https://en.wikipedia.org/wiki/Neuroinflammation|Neuroinflammatory]] effects due to excessive exposure to [[https://en.wikipedia.org/wiki/Manganese|manganese]] (Mn) were described as early as 1837 ([[#Couper|Couper, 1837]]), and is described as fundamental for the brain's innate [[https://en.wikipedia.org/wiki/Innate_immune_system|innate immune system]] to defend against foreign invasion. Chronic neuroinflammation however, when combined with [[https://en.wikipedia.org/wiki/Protein|protein]] misfolding and [[https://en.wikipedia.org/wiki/Mitochondrial_disease|mitochondrial impairment]] creates a neurotoxic environment, leads to self-perpetuating neuronal damage ([[#Araque|Araque et al, 2001]]; [[#Glass|Glass et al, 2010)]]; [[#Harischandra|Harischandra et al, 2019]]) occurring due to failure of auto-regulating mechanisms. Mn is able to pass through the [[https://en.wikipedia.org/wiki/Blood–brain_barrier|blood brain barrier]] initiating and propagating [[https://en.wikipedia.org/wiki/Proteopathy|disease-specific proteins]], entering [[https://en.wikipedia.org/wiki/Cell_(biology)|cells]] of the [[https://en.wikipedia.org/wiki/Central_nervous_system|central nervous system]] (CNS) by multiple complex transport systems as shown in <>[[#Fig_1|figure 1]]. playing a pivotal role in neuroinflammation.-~ ---- <> ---- == Effect of Mn on Microglia == ~-[[https://en.wikipedia.org/wiki/Microglia|Microglia]] are a form of [[https://en.wikipedia.org/wiki/Glia|glial cells]] within the [[https://en.wikipedia.org/wiki/Central_nervous_system|central nervous system]] (CNS), responsible for cerebral blood flow, [[https://en.wikipedia.org/wiki/Development_of_the_nervous_system|neural development]], regulation of synaptic function and brain metabolism ([[#Tjalkens|Tjalkens et al, 2017]]). During an inflammatory response microglia are activated to form an M1 [[https://en.wikipedia.org/wiki/Phenotype|phenotype]] which moves to the site of damage ([[#Tang|Tang et al, 2018]]). M1 inflammatory activation is regulated by the following proteins ([[#Tjalkens|Tjalkens et al, 2017]]):-~ * ~-[[https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase|Mitogen-activated protein kinase]]-~ * ~-[[https://en.wikipedia.org/wiki/AP-1_transcription_factor|Activator protein-1]]-~ * ~-[[https://en.wikipedia.org/wiki/Janus_kinase|Janus kinase]]-~ * ~-[[https://en.wikipedia.org/wiki/STAT_protein|Signal transducer and activator of transcription]]-~ * ~-[[https://en.wikipedia.org/wiki/Interferon_regulatory_factors|Interferon regulatory factors]]-~ * ~-Nuclear factor kappa B ([[https://en.wikipedia.org/wiki/NF-κB|NF-kB]])-~ ~-M1 microglial phenotypes respond to [[https://en.wikipedia.org/wiki/Damage-associated_molecular_pattern|damage-associated molecular patterns]] (DAMPs) such as basic fibroblast growth factor ([[https://en.wikipedia.org/wiki/Basic_fibroblast_growth_factor|FGF2]]) ([[#Woodbury_and_Ikezu|Woodbury and Ikezu, 2014]]; [[#Tang|Tang et al, 2018]]), released due to necrotic neurons, and are recognised by [[https://en.wikipedia.org/wiki/Pattern_recognition_receptor|pattern recognition receptors]] (PRRs) ([[#Husemann|Husemann et al, 2002]]). Activated M1 induce the release of [[https://en.wikipedia.org/wiki/Inflammatory_cytokine|pro-inflammatory factors]] ([[https://en.wikipedia.org/wiki/Inflammasome|inflammasomes]]) such as tumor necrosis factor alpha ([[https://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha|TNFα]]), interleukin-6 ([[https://en.wikipedia.org/wiki/Interleukin_6|IL-6]]), interleukin 1-alpha/beta ([[https://en.wikipedia.org/wiki/IL1A|IL-1α]]/[[https://en.wikipedia.org/wiki/Interleukin_1_beta|β]]), complement component 1q ([[https://en.wikipedia.org/wiki/Complement_component_1q|C1Q]]), and [[https://en.wikipedia.org/wiki/Reactive_oxygen_species|reactive oxygen species]] (ROS) ([[#Tjalkens|Tjalkens et al, 2017]]).-~ ~-Mn causes the activation of microglia in the [[https://en.wikipedia.org/wiki/Substantia_nigra|substantia nigra]] inducing M1 phenotype proliferation ([[#Verina|Verina et al., 2011]]). Mn affects M1 signalling pathways via [[https://en.wikipedia.org/wiki/P2Y_receptor|P2Y]] and [[https://en.wikipedia.org/wiki/P2X_purinoreceptor|P2X receptors]] which induce [[https://en.wikipedia.org/wiki/NF-κB|NF-kB]] transcription ([[#Park_and_Chun|Park and Chun, 2016]]). NF-kB transcription results in [[https://en.wikipedia.org/wiki/Nerve_growth_factor_IB|nerve growth factor IB]] expression which initiates pro-inflammatory factor release ([[#Tjalkens|Tjalkens et al, 2017]]) leading to [[https://en.wikipedia.org/wiki/Dopaminergic|dopaminergic]] neuronal damage and astrocyte activation via the [[https://en.wikipedia.org/wiki/Feedforward_neural_network?fbclid=IwAR17L6t0IThqK3aRw4mpwSP6899YIX_NmyyHTSlXETvVNpnLM4TTZ-qr3xA|feed-forward effect]] ([[#Zhang|Zhang et al., 2010]]).-~ ~-In addition, output of extracellular excitatory neurotransmitter [[https://en.wikipedia.org/wiki/Glutamate_(neurotransmitter)|glutamate]] is directly and indirectly increased by Mn induced M1 phenotype. Directly this is because of [[https://en.wikipedia.org/wiki/Cystine/glutamate_transporter|cystine/glutamate exchanger]] (xCT) dysfunction ([[#Kirdajova|Kirdajova et al, 2020]]) and [[https://en.wikipedia.org/wiki/Connexon|hemichannel]] gap junctions ([[#Umebayashi|Umebayashi et al, 2014]]). Indirectly this is due to their [[https://en.wikipedia.org/wiki/Feedforward_neural_network?fbclid=IwAR17L6t0IThqK3aRw4mpwSP6899YIX_NmyyHTSlXETvVNpnLM4TTZ-qr3xA|feed forward effect]] on astrocyte glutamate uptake ([[#Takaki|Takaki et al 2012]]). Glutamate accumulation results in [[https://en.wikipedia.org/wiki/Excitotoxicity|excitotoxicity]] ([[#Milewski|Milewski et al, 2019]]).-~ ---- == Effect of Mn on Astrocytes == || {{attachment:astrocyte.png|Cilia|width="500 height=500"}} <
><>'''[[#figure_2|Fig 2.]]'''<
>''Effect of inflammatory process on dopaminergic neurons '' <
>''(original image, based on image from [[#Wangfig|Wang et al (2009)]])'' || ~-[[https://en.wikipedia.org/wiki/Astrocyte|Astrocytes]] form the most abundant type of cells within the CNS, providing close contact with [[https://en.wikipedia.org/wiki/Microcirculation|microvasculature]] and neighbouring [[https://en.wikipedia.org/wiki/Neuron|neurons]] and forming physical barriers between neuronal synapses known as the [[https://en.wikipedia.org/wiki/Tripartite_synapse|tripartite synapse]]. Their close relationship enables active modulation of [[https://en.wikipedia.org/wiki/Synaptic_plasticity|synaptic plasticity]] via [[https://en.wikipedia.org/wiki/Gliotransmitter|gliotransmitter]] release, as well as homeostatic regulation and provisions of glucose and oxygen for neurons ([[#Tjalkens|Tjalkens et al, 2017]]).-~ ~-Glucose is stored as [[https://en.wikipedia.org/wiki/Glycogen|glycogen]] and [[https://en.wikipedia.org/wiki/Glutamate_(neurotransmitter)|glutamate]], the latter is [[https://en.wikipedia.org/wiki/Transamination|transaminated]] into [[https://en.wikipedia.org/wiki/Glutamine|glutamine]], used in the neuronal [[https://en.wikipedia.org/wiki/Glutamate–glutamine_cycle|glutamate-glutamine cycle]] enabling [[https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid|gamma aminobutyric acid]] (GABA) production. Excess [[https://en.wikipedia.org/wiki/Neurotransmitter|neurotransmitter]] glutamate released in neuronal [[https://en.wikipedia.org/wiki/Synapse|synapses]] are taken up by astrocytes reducing [[https://en.wikipedia.org/wiki/Excitotoxicity|excitotoxicity]] in neurons ([[#Tjalkens|Tjalkens et al, 2017]]).-~ ~-In addition, [[https://en.wikipedia.org/wiki/Lactic_acid|lactate]] produced by astrocytes forms [[https://en.wikipedia.org/wiki/Adenosine_triphosphate|adenosine triphosphate]] (ATP) and [[https://en.wikipedia.org/wiki/Pyruvic_acid|pyruvate]] in neurons via the [[https://en.wikipedia.org/wiki/Citric_acid_cycle|citric acid cycle]] ([[#Tjalkens|Tjalkens et al, 2017]]).-~ ~-Astrocytes are pivotal to the [[https://en.wikipedia.org/wiki/Blood–brain_barrier|blood-brain barrier]], forming a semipermeable border between brain parenchyma and vasculature due to their astrocytic end feet, preventing solutes from non-selectively crossing into the CNS ([[#Tjalkens|Tjalkens et al, 2017]]). Mn can move across the blood-brain barrier ([[#Yang|Yang et al, 2018]]).-~ ~-Due to their ability to accumulate high levels of Mn they play an important role in Mn associated [[https://en.wikipedia.org/wiki/Neuroinflammation|neuroinflammation]] ([[#Tjalkens|Tjalkens et al, 2017]]; [[#Yang|Yang et al, 2018]]). [[#Spranger|Spranger et al (1998)]] found that astrocytes cannot cause neuronal [[https://en.wikipedia.org/wiki/Apoptosis|apoptosis]] in response to Mn without [[https://en.wikipedia.org/wiki/Inflammatory_cytokine|pro-inflammatory factors]] produced by microglia ([[#Araque|Araque et al, 2001]]; [[#Park_and_Chun|Park and Chun, 2016]]; [[#Tjalkens|Tjalkens et al, 2017]]).-~ ~-[[https://en.wikipedia.org/wiki/Damage-associated_molecular_pattern|DAMPs]] released by injured neurons and [[https://en.wikipedia.org/wiki/Inflammatory_cytokine|pro-inflammatory factors]] released by M1 microglia cause the activation of astrocytes due to [[https://en.wikipedia.org/wiki/Pattern_recognition_receptor|PRRs]] promoting [[https://en.wikipedia.org/wiki/Inflammation|inflammation]] ([[#Glass|Glass et al, 2010]]; [[#Tjalkens|Tjalkens et al, 2017]]).These factors result in [[https://en.wikipedia.org/wiki/Glial_scar|glial scar]] formation known as [[https://en.wikipedia.org/wiki/Astrogliosis|astrogliosis]] within the [[https://en.wikipedia.org/wiki/Basal_ganglia|basal ganglia]] ([[#Tjalkens|Tjalkens et al, 2017]]). Astrogliosis leads to the proliferation of the [[https://en.wikipedia.org/wiki/Astrogliosis|reactive astrocyte]] (A1) phenotype ([[#Liddelow|Liddelow et al, 2017]]). Resting A2 astrocyte phenotypes promote neural tissue repair and survival by upregulation of [[https://en.wikipedia.org/wiki/Neurotrophic_factors|neurotrophic factors]] whereas A1 proliferation leads to a lack of normal functions which is [[https://en.wikipedia.org/wiki/Neurotoxicity|neurotoxic]] to both neurons and [[https://en.wikipedia.org/wiki/Oligodendrocyte|oligodendrocytes]] ([[#Liddelow|Liddelow et al, 2017]]).-~ ~-Astrocyte [[https://en.wikipedia.org/wiki/Cystine/glutamate_transporter|cystine-glutamate exchangers]] (xCT) cause efflux of glutamate and the influx of cystine, a precursor for the antioxidant [[https://en.wikipedia.org/wiki/Glutathione|glutathione]] (GSH), produced internally ([[#Kitagawa|Kitagawa et al, 2019]]). GSH reduces [[https://en.wikipedia.org/wiki/Oxidative_stress|oxidative stress]] by scavenging of [[https://en.wikipedia.org/wiki/Reactive_oxygen_species|ROS]] ([[#Yang|Yang et al, 2018]]). Mn activated A1s exhibit an increase in astrocyte [[https://en.wikipedia.org/wiki/Glutaminase|glutaminase]] expression, as well as glutamate transporter excitatory amino acid carrier-1 ([[https://en.wikipedia.org/wiki/Glutamate_transporter|EAAC1]]) and xCT dysfunction. These dysfunctions result in glutamate accumulation and GSH synthesis inhibition increasing oxidative stress ([[#Xu|Xu et al, 2010]]; [[#Yang|Yang et al, 2018]]), causing astrocytes to become mediators in the excitotoxic events of inflammation ([[#Milewski|Milewski et al, 2019]]).-~ ~-Mn activation of [[https://en.wikipedia.org/wiki/P2Y_receptor|P2Y receptors]] and alteration of [[https://en.wikipedia.org/wiki/TRPC3|TRPC3]] cation channels disrupts ATP dependent calcium signalling in astrocyte membranes leading to local [[https://en.wikipedia.org/wiki/Hypoxia_(medical)|hypoxia]] due to release of [[https://en.wikipedia.org/wiki/Vasoactivity|vasoactive]] compounds and insufficient metabolic support ([[#Tjalkens|Tjalkens et al, 2017]]). These effects lead to depolarisation of cell membranes, calcium ion overload, and increased extracellular glutamate production ([[#Kirdajova|Kirdajova et al, 2020]]).-~ ~-According to [[#Yang|Yang et al (2018)]] additional astrocytic changes in response to Mn include:-~ * ~-[[https://en.wikipedia.org/wiki/Translocator_protein|Increased peripheral-type benzodiazepine receptor]](PTBR) binding sites in mitochondria-~ * ~-[[https://en.wikipedia.org/wiki/Cerebral_edema|Cytotoxic oedema]] due to [[https://en.wikipedia.org/wiki/Aquaporin_4|Aquaporin 4]] (AQP4) channels-~ * ~-[[https://en.wikipedia.org/wiki/Nucleolus|Nucleolus]] collapse-~ * ~-Intense [[https://en.wikipedia.org/wiki/Chromatin|chromatin]] condensation-~ * ~-Increased activity of [[https://en.wikipedia.org/wiki/Glyceraldehyde_3-phosphate_dehydrogenase|glyceraldehyde 3-phosphate dehydrogenase]] (GAPDH) initiating [[https://en.wikipedia.org/wiki/Apoptosis|apoptosis]]-~ * ~-Inhibition of [[https://en.wikipedia.org/wiki/Glutamine_synthetase|glutamine synthetase enzyme]] ([[#Verkhratsky|Verkhratsky et al, 2016]])-~ * ~-Increased [[https://en.wikipedia.org/wiki/Reactive_nitrogen_species|reactive nitrogen species]](RNS) production, due to [[https://en.wikipedia.org/wiki/Arginine|L-Arginine]] uptake, [[https://en.wikipedia.org/wiki/Nitric_oxide_synthase#iNOS|inducible nitric oxide synthase]] (iNOS) and stimulation of [[https://en.wikipedia.org/wiki/NF-κB|NF-kB]] as a result of [[https://en.wikipedia.org/wiki/Cytokine|inflammatory cytokine]] modulation ([[#Moreno|Moreno et al, 2008]]; [[#Zhang|Zhang et al, 2010]])-~ ~-ROS and RNS increase vulnerability of [[https://en.wikipedia.org/wiki/Dopaminergic_cell_groups|dopaminergic cell groups]] to Mn induced toxicity ([[#Zhang|Zhang et al, 2010]]), contributing towards neuronal-induced cell death (see <>[[#Fig_2|figure 2]]) by [[https://en.wikipedia.org/wiki/Nitrosylation|nitrosylation]] and [[https://en.wikipedia.org/wiki/Nitration|nitration]] of protein residues ([[#Tjalkens|Tjalkens et al, 2017]]).-~ ~-In addition to the effect of microglia on astrocytes, astrocytes perpetuate microglial activation by the crosstalk [[https://en.wikipedia.org/wiki/Feedforward_neural_network?fbclid=IwAR17L6t0IThqK3aRw4mpwSP6899YIX_NmyyHTSlXETvVNpnLM4TTZ-qr3xA|feed forward effect]] ([[#Glass|Glass et al, 2010]]; [[#Kokaia|Kokaia et al, 2012]]).-~ ~-[[#Bhatia|Bhatia et al (2019)]] found that, if introduced in an increasing manner, healthy astrocytes and neurons in the absence of pro-inflammatory microglia are capable of moderate toleration of [[https://en.wikipedia.org/wiki/Oxidative_stress|oxidative stress]], allowing astrocytes to fulfil their neuroprotective role. However these astrocytes are A2 phenotypes, suggesting that induced A1 phenotypic astrocytes may not be as tolerant.-~ ---- == Effect of Mn on Mitochondria == ~-Mn concentration is highest in [[https://en.wikipedia.org/wiki/Mitochondrion|mitochondria]] [[#Morello|Morello et al, 2008]]. Mn sequestered by astrocyte mitochondria inhibits [[https://en.wikipedia.org/wiki/Oxidative_phosphorylation|oxidative phosphorylation]], causing [[https://en.wikipedia.org/wiki/Oxidative_stress|oxidative stress]] by increased production of [[https://en.wikipedia.org/wiki/Reactive_oxygen_species|ROS]] ([[#Barhoumi|Barhoumi et al, 2004]]). Increased [[https://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha|TNFα]] cytokines released by the cell as seen in manganism triggers [[https://en.wikipedia.org/wiki/Depolarization|membrane depolarization]], further perpetuating ROS production, accumulating [[https://en.wikipedia.org/wiki/PINK1|PTEN-induced kinase 1]](PINK1) and decreasing ATP generation ([[#Cho|Cho et al, 2020]]). Reduced ATP availability and mitochondrial metabolic function are a direct result from Mn induced neuroinflammation ([[#Cho|Cho et al, 2020]]).-~ ~-Due to [[https://en.wikipedia.org/wiki/Hypercalcaemia|calcium overload]] within cells following neuroinflammatory changes [[https://en.wikipedia.org/wiki/Mitochondrial_permeability_transition_pore|mitochondria permeability transition pores]] (mPTP) develop within mitochondrial membranes ([[#Kirdajova|Kirdajova et al, 2020]]), enabling the release of pro-apoptotic factors such as [[https://en.wikipedia.org/wiki/Cytochrome_c|cytochrome C]], [[https://en.wikipedia.org/wiki/Apoptosis-inducing_factor|apoptosis-inducing factor]] (AIF) and [[https://en.wikipedia.org/wiki/Diablo_homolog|Diablo]] ([[#Yang|Yang et al, 2018]]). These factors result in cell apoptosis.-~ ~-Damaged mitochondria fuse to healthy mitochondria by [[https://en.wikipedia.org/wiki/Tunneling_nanotube|tunneling nanotube]] formation ([[#Torralba|Torralba et al, 2016]]) or undergo mitochondrial fission to eliminate themselves from cells by [[https://en.wikipedia.org/wiki/Mitophagy|mitophagy]] ([[#Cho|Cho et al, 2020]]). Astrocytes release functional mitochondria towards neurons via a calcium dependent mechanism in response to a stroke, delaying excitotoxic cell death and contributing towards a [[https://en.wikipedia.org/wiki/Neuroprotection|neuroprotective]] role ([[#Kirdajova|Kirdajova et al, 2020]]). Additionally, upregulation of [[https://en.wikipedia.org/wiki/Translocator_protein|peripheral-type benzodiazepine receptor]] binding sites as well as increased neurosteroid synthesis is seen in astrocyte mitochondria after Mn exposure, this is believed to be due to attempted mitochondrial repair following neuroinflammatory damage ([[#Yang|Yang et al, 2018]]).-~ ---- == Neuroinflammatory diseases == === Manganism, Parkinson’s disease and manganese induced parkisonism === || {{attachment:mn_induced_PD.png|Cilia|width="400 height=350"}} <
><>'''[[#figure_3|Fig 3.]]'''<
>'' Manganism and manganese induced Parkison's disease'' <
>''(based on an image from [[#Lucchinifig|Lucchini et al (2009)]]'' || ~-Manganism is a result of excessive or chronic inhalation of Mn ([[#Kwakye|Kwakye et al,2015]]). [[https://en.wikipedia.org/wiki/Natural_resistance-associated_macrophage_protein_2|DMT1]] in the [[https://en.wikipedia.org/wiki/Olfactory_epithelium|olfactory epithelium]] provides access to the [[https://en.wikipedia.org/wiki/Olfactory_nerve|olfactory nerve]], leading to basal ganglia and other DTM1 rich structures of the CNS ([[#Harischarda|Harischarda et al 2019]]).-~ ~-While [[https://en.wikipedia.org/wiki/Manganism|Manganism]] and [[https://en.wikipedia.org/wiki/Parkinson's_disease|Parkinson’s disease]] are different, they share many similarities. Both affect the [[https://en.wikipedia.org/wiki/Pars_compacta|substantia nigra pars compacta]] (SNpc) and cause neuroinflammation followed by dopaminergic cell death ([[#Andruska_and_Racette|Andruska and Racette, 2015]]; [[#Wang|Wang et al, 2015]]). Microglial activation is frequently observed during post mortem research of Parkison's disease ([[#Wang|Wang et al, 2015]]), correlating to the effect of Mn on microglia through [[https://en.wikipedia.org/wiki/NF-κB|NF-kB]] and [[https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase|MAPK]] pathways ([[#Tjalkens|Tjalkens et al 2017]]).-~ ~-[[https://en.wikipedia.org/wiki/Extrapyramidal_symptoms|Extrapyramidal symptoms]] result in both diseases, although tremors are not as severe or frequent in Manganism. Individuals with Manganism have the tendency to fall backwards, [[https://en.wikipedia.org/wiki/Hypersalivation|hypersalivate]], and [[https://en.wikipedia.org/wiki/Plantar_reflex|Babinski-like responses]] can be observed more frequently than in Parkison's disease ([[#Harischandra|Harischandra et al, 2019]]).-~ ~-[[https://en.wikipedia.org/wiki/Alpha-synuclein|α-synuclein]] is believed to play a role in Parkison's disease, when misfolded or an excessive amount gets released from the degenerating dopaminergic cells, microglia release cytokines enhancing the inflammatory response. ([[#Wang|Wang et al, 2015]]). According to [[#Harischarda|Harischarda et al (2019)]] a long term exposure to Mn can also result in increased [[https://en.wikipedia.org/wiki/Protein_folding#Incorrect_protein_folding_and_neurodegenerative_disease|misfolding]] of α-synuclein leading to aggregation and [[https://en.wikipedia.org/wiki/Amyloid|amyloid]] formation.-~ ~-Previously Manganism was commonly caused by high exposure of Mn, typically through[[https://en.wikipedia.org/wiki/Category:Manganese_minerals|mining]], however chronic low dose exposure is more typical today. It is theorized that chronically acquired toxicity may increase the risk of developing Parkison's disease (see <>[[#Fig_3|figure 3]]). Chronic low dose toxicity may be acquired through external exposure, genetic mutation of Mn regulation (e.g. transport proteins [[https://en.wikipedia.org/wiki/ATP13A2|ATP13A2]] and [[https://en.wikipedia.org/wiki/Solute_carrier_family_30_member_10|SLC30A10]]) or liver failure ([[#Lucchini|Lucchini et al 2009]]). Children ingesting high levels of [[https://en.wikipedia.org/wiki/Manganese|manganese]] have shown to be at higher risk to develop [[https://en.wikipedia.org/wiki/Cognitive_disorder|cognitive dysfunction]] due to higher gastrointestinal absorption and lower liver excretion ([[#Tjalkens|Tjalkens et al, 2019]]).-~ === Hepatic encephalopathy === ~-An important development of impaired [[https://en.wikipedia.org/wiki/Liver|liver]] function is [[https://en.wikipedia.org/wiki/Hepatic_encephalopathy|hepatic encephalopathy]] (HE). While [[https://en.wikipedia.org/wiki/Ammonia|ammonia]] and its effect on [[https://en.wikipedia.org/wiki/Astrocyte|astrocytes]] is suspected to be the primary cause for HE, it can not account for all symptoms. Activation of [[https://en.wikipedia.org/wiki/Microglia|microglia]] resulting in [[https://en.wikipedia.org/wiki/Inflammatory_cytokine|proinflammatory cytokines]] release plays a significant role in the early development of HE. Although ammonia-cytokine [[https://en.wikipedia.org/wiki/Synergy|synergism]] has been observed to increase neuroinflammatory effect, ammonia has little effect on the microglial activation ([[#Prakash_and_Mullen|Prakash and Mullen, 2010]]) unlike Mn ([[#Butterworth|Butterworth, 2013]]).-~ ~-Mn excretion occurs due to liver metabolism, whereby it enters the liver from the blood through the [[https://en.wikipedia.org/wiki/Hepatic_portal_system|portal system]] and is recirculated into the [[https://en.wikipedia.org/wiki/Gastrointestinal_tract|gastrointestinal]] tract. Within the gastrointestinal tract 1-5% is reabsorbed, and the majority is excreted in faeces. ([[#Davis|Davis et al, 1993]]; [[#Aschner_and_Aschner|Aschner and Aschner, 2005]]). Lack of liver metabolism due to disease, such as [[https://en.wikipedia.org/wiki/Cirrhosis|cirrhosis]] or [[https://en.wikipedia.org/wiki/Portosystemic_shunt|portosystemic shunt]] (PSS) may lead to the accumulation of Mn in blood. A study by [[#Prakash_and_Mullen|Prakash and Mullen, 2010]] found that levels of Mn in the brain were increased by chronic liver failure but not the acute form ([[#Butterworth|Butterworth, 2013]]), this was confirmed by [[https://en.wikipedia.org/wiki/Parkinson's_disease|Parkison's disease]] like symptoms in human patients with HE, caused by either cirrhosis and PSS ([[#Prakash_and_Mullen|Prakash and Mullen, 2010]]).-~ ~-Various dog and cat breeds suffer from congenital PSS, putting them at risk of developing HE. Dog breeds include ([[#Van_den_Bossche|Van den Bossche et al, 2012]]):-~ * ~-[[https://en.wikipedia.org/wiki/Cairn_Terrier|Cairn terrier]]-~ * ~-[[https://en.wikipedia.org/wiki/Yorkshire_Terrier|Yorkshire terrier]]-~ * ~-[[https://en.wikipedia.org/wiki/Jack_Russell_Terrier|Jack Russell terrier]]-~ * ~-[[https://en.wikipedia.org/wiki/Dachshund|Dachshund]]-~ * ~-[[https://en.wikipedia.org/wiki/Maltese_(dog)|Maltese]]-~ ~-[[https://en.wikipedia.org/wiki/Magnetic_resonance_imaging|MRI]] images of [[https://en.wikipedia.org/wiki/Basal_ganglia|basal ganglia]] of patients with HE, as well as observed [[https://en.wikipedia.org/wiki/Dopaminergic|dopaminergic]] [[https://en.wikipedia.org/wiki/Apoptosis|apoptosis]] suggested Mn involvement. Due to the effect of Mn on the activation of [[https://en.wikipedia.org/wiki/Microglia|microglial cells]] causing neuroinflammation chronic liver failure can be linked with neuroinflammation due to manganese accumulation ([[#Butterworth|Butterworth, 2013]]).-~ === Alzheimers Disease === ~-High Mn levels in the CNS of patients with Alzheimer's disease suggest that Mn might be a risk factor. Overexposure of Mn and other metals can cause changes in [[https://en.wikipedia.org/wiki/Amyloid_beta|amyloid-β]] aggregation in the frontal cortex, hinting towards cognitive and memory defects ([[#Ijomone|Ijomone et al, 2019]]).-~ ~-Mn induces oxidative stress mostly in astrocytes by promoting [[https://en.wikipedia.org/wiki/Reactive_oxygen_species|ROS]] due to mitochondrial respiratory chain dysfunction. Consequently, inhibition of antioxidant production and calcium signal changes occur. Resulting decreased mitochondrial activity and increased calcium levels within the mitochondria leads to neuron apoptosis, thought to cause neurodegeneration ([[#Ijomone|Ijomone et al, 2019]]). Mn induced apoptosis involves [[https://en.wikipedia.org/wiki/PRKCD|PKC-δ]], an enzyme involved in Alzheimer's, Parkinson’s and prion diseases ([[#Harischarda|Harischarda et al, 2019]]). According to a study by [[#Du|Du et al (2018)]] PKC-δ levels were high in patients with Alzheimer’s, this link was confirmed by reduction of amyloid-β levels due to inhibition of PKC-δ.-~ ~-While Alzheimers disease is commonly known to be a human disease, alzheimer like neurodegeneration has been observed in [[https://en.wikipedia.org/wiki/Dolphin|dolphins]], [[https://en.wikipedia.org/wiki/Sea_lion|sea lions]] and to lesser extents, [[https://en.wikipedia.org/wiki/Cat|cats]] ([[#Gunn-More|Gunn-More et al, 2018]]). More research is required to understand the link between high Mn levels and Alzheimer's.-~ === Manganese and prion disease === ~-[[https://en.wikipedia.org/wiki/Prion#Diseases|Prion diseases]] are lethal transmissible neurodegenerative diseases with long incubation times, caused by misfolding of proteins and lead to high neuronal cell death in specific regions of the [[https://en.wikipedia.org/wiki/Central_nervous_system|CNS]]. Prions must be ingested to enable transmission and exist as different variants such as [[https://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy|BSE]] in cattle and [[https://en.wikipedia.org/wiki/Scrapie|scrapie]] in sheep ([[#Hesketh|Hesketh et al, 2007]]).-~ ~-Studies have shown that prion diseases can be caused by an excess intake and accumulation of Mn in the central nervous system (CNS) ([[#Hesketh|Hesketh et al, 2007]]). When Mn binds to the protein, it changes its conformation from an [[https://en.wikipedia.org/wiki/Alpha_helix|α-helical]] form to a protein rich in [[https://en.wikipedia.org/wiki/Beta_sheet|β-pleated sheets]]. Mn induced conformational changes show a high resistance to protease enzymes, alter metal binding sites and result in loss of functionality. Due to changes in metal binding sites, [[https://en.wikipedia.org/wiki/Copper|copper]] (Cu) cannot bind to the [[https://en.wikipedia.org/wiki/PRNP|prion protein]] (PrP), resulting in changes in the metal composition of the CNS ([[#Hesketh|Hesketh et al, 2007]]).-~ ~-The misfolded PrP has been found to survive well in soil matrices and even longer in the presence of Mn. PrP enters the soil via farm effluent, carcasses, or infected meat products, and can remain in the soil for up to three years ([[#Davis_and_Brown|Davis and Brown, 2009]]). PrP have a high binding affinity to Cu and Mn, this is believed to be the cause of the high stability of the PrP in soil ([[#Davis_and_Brown|Davis and Brown, 2009]]). [[#Davis_and_Brown|Davis and Brown (2009)]] found a link between areas of high scrapie incidence and higher Mn than Cu concentration in the nearby grazing. In a study by [[#Mitteregger|Mitteregger et al, (2019)]] a PrP responsible for the [[https://en.wikipedia.org/wiki/Transmissible_spongiform_encephalopathy|transmissible spongiform encephalopathy]](TSE), scrapie in [[https://en.wikipedia.org/wiki/Mouse|mice]] increased in [[https://en.wikipedia.org/wiki/Pathogen|pathogenicity]] when experimental animals were fed a high Mn low Cu diet, and a decrease in the PrP pathogenicity when fed a low Mn high Cu diet.-~ ~-Increased Mn within the CNS elicits a neuroinflammatory response resulting in [[https://en.wikipedia.org/wiki/Astrogliosis|astrogliosis]], [[https://en.wikipedia.org/wiki/Toxic_vacuolation|vacuolation]], and neuronal loss ([[#Mitteregger|Mitteregger et al, 2019]]; [[#Carroll_and_Chesebro|Carroll and Chesebro, 2019]]). It is believed that the symptoms associated with prion disease and subsequent disease progression are due to these neuroinflammatory effects ([[#Carroll_and_Chesebro|Carroll and Chesebro, 2019]]).-~ ---- == Mn accumulation in different species == ~-Increased inflammatory genes have been measured in rodent and non-human primate studies of Mn exposure ([[#Moreno|Moreno et al, 2008]]; [[#Verina|Verina et al, 2011]]). An experiment by [[#Bock|Bock et al (2008)]] on [[https://en.wikipedia.org/wiki/Marmoset|marmosets]] and [[https://en.wikipedia.org/wiki/Rat|rats]] demonstrated different levels of Mn accumulation patterns in brain areas between these two species. Marmosets showed accumulation of Mn in more brain structures than rats which showed accumulation within the [[https://en.wikipedia.org/wiki/Striatum|striatum]] and the [[https://en.wikipedia.org/wiki/Basal_ganglia|basal ganglia]] ([[#Xu|Xu et al. 2010]]), this is hypothesised as being because of [[https://en.wikipedia.org/wiki/Ventricular_system|ventricle]] differences between species. Most current information has been obtained using rodent models ([[#Tjalkens|Tjalkens et al, 2017]]).-~ ---- == Neuroinflammatory treatment targets == ~-Current proposed targets for neuroinflammation treatment are the following:-~ * ~-[[https://en.wikipedia.org/wiki/NF-κB#Inhibitors_of_NF-κB_activity|NF-kB inhibition]] ([[#Alcamo|Alcamo et al, 2001]]).-~ * ~-[[https://en.wikipedia.org/wiki/Nerve_growth_factor_IB|NGFIB]] receptors which results in NF-kB inhibition ([[#Tjalkens|Tjalkens et al, 2017]]).-~ * ~-[[https://en.wikipedia.org/wiki/P2Y12|P2Y12]] inhibition causes down-regulation of NF-kB ([[#Tjalkens|Tjalkens et al, 2017]]).-~ * ~-INI0602, a [[https://en.wikipedia.org/wiki/Gap_junction|gap junction]] hemichannel inhibitor has been found to suppress Alzheimer’s disease progression ([[#Umebayashi|Umebayashi et al, 2014]]).-~ * ~-[[https://en.wikipedia.org/wiki/Dizocilpine|MK-801]]MK-801 a non-competitive [[https://en.wikipedia.org/wiki/NMDA_receptor|NMDA receptor]] [[https://en.wikipedia.org/wiki/Receptor_antagonist|antagonist]] has been shown to reduce [[https://en.wikipedia.org/wiki/Glutamate_(neurotransmitter)|glutamate]] binding ([[#Xu|Xu et al. 2010]]).-~ * ~-[[https://en.wikipedia.org/wiki/Cystine/glutamate_transporter|xCT]] system ([[#Kitagawa|Kitagawa et al, 2019]]).-~ * ~-[[https://en.wikipedia.org/wiki/Role_of_microglia_in_disease#Inhibition_of_cytokine_synthesis|Microglial cytokine inhibitino]] ([[#Liddelow|Liddelow et al, 2017]]).-~ * ~-[[https://en.wikipedia.org/wiki/CX3CL1|CX3CL1]] [[https://en.wikipedia.org/wiki/Chemokine|chemokine]] activation ([[#Limatola_and_Ransohoff|Limatola and Ransohoff, 2014]]).-~ * ~-[[https://en.wikipedia.org/wiki/Basic_fibroblast_growth_factor|FGF2]] significantly (P>0.05) reverses [[https://en.wikipedia.org/wiki/Depression_(mood)|depressive behaviours]], [[https://en.wikipedia.org/wiki/CX3CL1|CX3CL1]] inhibition and microglial proliferation ([[#Tang|Tang et al, 2018]]).-~ * ~-[[https://en.wikipedia.org/wiki/Glial_fibrillary_acidic_proteinhttps://en.wikipedia.org/wiki/Glial_fibrillary_acidic_protein|GFAP]] has been associated with lesion minimisation in response to stroke and [[https://en.wikipedia.org/wiki/Autoimmune_disease|autoimmune]] [[https://en.wikipedia.org/wiki/Encephalomyelitis|encephalomyelitis]] risk ([[#Tjalkens|Tjalkens et al, 2017]]).-~ * ~-Mice lacking the [[https://en.wikipedia.org/wiki/Nitric_oxide_synthase#iNOS|inducible form]] of [[https://en.wikipedia.org/wiki/Nitric_oxide_synthase|nitrogen monoxide synthase]] are deemed to be protected from neurotoxicity induced by Mn. 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Authors own. Adapted from Wang et al, (2015)]]-~ ~-<> Figure.3. [[Manganism and manganese induced Parkison's disease. 2020 Authors own. Adapted from Lucchini et al (2009)]]-~ ----