Estratégias anti-inflamatórias para encefalopatia hepática: estudos pré-clínicos

Santos, Rafaela Pinto Coelho; Toscano, Eliana Cristina de Brito; Rachid, Milene Alvarenga

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Arquivos de Neuro-Psiquiatria

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Sumário

View and Review • Arq. Neuro-Psiquiatr. 81 (7) • 2023 • https://doi.org/10.1055/s-0043-1767819 copiar

Estratégias anti-inflamatórias para encefalopatia hepática: estudos pré-clínicos

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

A encefalopatia hepática (EH) é uma síndrome neuropsiquiátrica potencialmente reversível. Muitas vezes a EH causa disfunções cognitivas e motoras devido à insuficiência do fígado ou por um desvio entre a veia porta hepática e a vasculatura sistêmica. O dano no fígado provoca alterações periféricas, como no metabolismo e nas respostas inflamatórias periféricas, que desencadeiam uma neuroinflamação exacerbada. Em modelos experimentais, estratégias anti-inflamatórias têm demonstrado efeitos neuroprotetores, levando a uma redução dos prejuízos cognitivos e motores relacionados à EH. Neste cenário, evidências crescentes têm mostrado a inflamação periférica e no sistema nervoso central como um promissor alvo pré-clínico. Nesta revisão, abordamos uma visão geral de drogas e compostos naturais aprovados pelo FDA para o uso no tratamento de outras doenças neurológicas e não neurológicas, que tiveram papel neuroprotetor na EH experimental, pelo menos em parte, através de mecanismos anti-inflamatórios. Apesar dos resultados empolgantes em modelos animais, os dados avaliados devem ser criticamente interpretados, destacando a importância da tradução dos achados para ensaios clínicos.

Palavras-chave
Encefalopatia Hepática; Doenças Neuroinflamatórias; Neuroproteção; Modelos Animais

Drug	Action	HE Model	Peripheral parameters and systemic inflammation	Central parameters and neuroinflammation	Behavioral, cognitive, and motor parameters	Reference
Minocycline i.p. ^{A, B}	Antibiotic	Male Sprague–Dawley rats. ALF: Portocaval anastomosis + hepatic arterial ligation Male Albino rats: Galactosamine-induced ALF	↓ AST, ALT ↓ Ammonia	↓ Microglial activation ^A ↑ IL-10 ^B ↓ IL-1β, IL-6, TNF-α ^B ↓ IL-1β, IL-6, TNF-α _mRNA ^A ↓ Nitrite/Nitrate ^B ↓ iNOS, heme oxygenase-1 gene expression ^B ↓ Brain water ^B ↓ Brain edema ^A	+ Time to loss of righting and corneal reflex	A: Jiang et al., 2009⁵⁷57 Jiang W, Desjardins P, Butterworth RF. Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. J Neurochem 2009;109 (02):485–493. Doi: 10.1111/j.1471-4159.2009.05981.x https://doi.org/10.1111/j.1471-4159.2009... B: Gamal et al., 2013⁵⁸58 Gamal M, Abdel Wahab Z, Eshra M, Rashed L, Sharawy N. Comparative Neuroprotective Effects of Dexamethasone and Minocycline during Hepatic Encephalopathy. Neurol Res Int 2014;2014:254683
Dexamethasone i.p.	Corticosteroid	Male Albino rats: Galactosamine-induced ALF	↓ AST, ALT ↓ Ammonia	↑ IL-10 ↓ IL-1β, IL-6, TNF-α ↓ Nitrite/Nitrate ↓ iNOS, heme oxygenase-1 NA: Brain water		Gamal et al., 2013⁵⁸58 Gamal M, Abdel Wahab Z, Eshra M, Rashed L, Sharawy N. Comparative Neuroprotective Effects of Dexamethasone and Minocycline during Hepatic Encephalopathy. Neurol Res Int 2014;2014:254683
Etanercept (ETA) i.p.	Anti TNF- α	Male C57/BL6 mice AOM-induced AFL	↓ AST, ALT ↓ Ammonia, TNF-α, IL-6, ↑ GSH + Liver histology: ↓ necrosis, vacuolization hepatocyte and congestion	↓ Microglia ↓ IL-6 NA: GSH	↑Time to coma	Chastre et al., 2012⁶³63 Chastre A, Bélanger M, Beauchesne E, Nguyen BN, Desjardins P, Butterworth RF. Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liver failure and its neurological complications. PLoS One 2012;7(11): e49670
Infliximab i.v. tail ^{A, B}	Anti TNF-α	Male Wistar rats: PCS ^{A, B}	NA: Ammonia ^{A, B} ↓ PGE2, IL-6 ^{A, B} ↓ IL-17 ^A ↑ IL-10 ^{A, B} NA: IL-4 ^B	• Cerebellum ^B: ↓ Microglia and astrocyte activation ↓ cell expressing TNF- α, IL-1β ↓ [TNF- α, IL-1β] Modulate GABA and GABA transporter in astrocyte and neuron • Hippocampus ^A: ↓ Microglia activation ↓ Neuron expressing TNF- α NA: cell expressing IL-1β ↓ TNF-α _mRNA ↓ [TNF-α, IL-1β] Modulate Glu receptors in brain regions	+ Spatial memory ^A + Learning ability ^B + Motor coordination ^B	A : Dadsetan et al., 2016a²²22 Dadsetan S, Balzano T, Forteza J, et al. Reducing Peripheral Inflammation with Infliximab Reduces Neuroinflammation and Improves Cognition in Rats with Hepatic Encephalopathy. Front Mol Neurosci 2016;9:106 B: Dadsetan et al., 2016b⁶⁴64 Dadsetan S, Balzano T, Forteza J, et al. Infliximab reduces peripheral inflammation, neuroinflammation, and extracellular GABA in the cerebellum and improves learning and motor coordination in rats with hepatic encephalopathy. J Neuroinflammation 2016;13 (01):245
Ibuprofen i.p. ^{A, B, C}	NSAID	Male Wistar rats^{A, B, C, D}: PCS ^{A, B, C} BDL ^D Hyperammonemic diet ^D	NA: Ammonia ^B	• Cerebral cortex: Modulate Glu pathways ^B NA: [TNF- α, IL-6] ^B ↓ iNOS and COX activity ^B • Striatum: ↓ PREP activity ^A • SNr: Modulate Glu and Glu transporters ^C • Cerebellum: NA: iNOS ^D ↓ MHCII ^D NA: Ammonia ^D	+ Learning ability ^{B, D} + Cognitive function ^D + Motor activity ^{C, D}	A: Tenorio-Laranga et al., 2015⁶²62 Tenorio-Laranga J,Montoliu C, Urios A, et al. The expression levels of prolyl oligopeptidase responds not only to neuroinflammation but also to systemic inflammation upon liver failure in rat models and cirrhotic patients. J Neuroinflammation 2015;12:183B: Cauli et al., 2007⁵⁹59 Cauli O, Rodrigo R, Piedrafita B, Boix J, Felipo V. Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts. Hepatology 2007;46(02):514–519. Doi: 10.1002/hep.21734 https://doi.org/10.1002/hep.21734... C: Cauli et al., 2009⁶¹61 Cauli O, Rodrigo R, Piedrafita B, Llansola M, MansouriMT, Felipo V. Neuroinflammation contributes to hypokinesia in rats with hepatic encephalopathy: ibuprofen restores its motor activity. J Neurosci Res 2009;87(06):1369–1374. Doi: 10.1002/jnr.21947 https://doi.org/10.1002/jnr.21947... D: Rodrigo et al., 2010⁶⁰60 Rodrigo R, Cauli O, Gomez-Pinedo U, et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 2010;139(02):675–684. Doi: 10.1053/j.gastro.2010.03.040 https://doi.org/10.1053/j.gastro.2010.03...
Losartan gavage	ARB	Male Sprangue-Dawley rats: TAA-induce CLF: MHE	↓ Ammonia, ALT, GGT, MDA ↓ TNF- α_mRNA ↑ GSH + Liver histology ↓ Liver fibrosis	–	NA: Psycomotor behavior NA: Locomotory activity	Murad et al., 2017⁶⁵65 Murad HA, Gazzaz ZJ, Ali SS, Ibraheem MS. Candesartan, rather than losartan, improves motor dysfunction in thioacetamideinduced chronic liver failure in rats. Braz J Med Biol Res 2017;50(11):e6665 Epub 2017/09/28. doi: 10.1590/1414-431X20176665. PubMed PMID: 28953991; PubMed Central PMCID: PMCPMC5609604. https://doi.org/10.1590/1414-431X2017666...
Sildenafil drinking water ^{A, B, C}	PDE-5 inhibitor	Male Wistar rats ^{A, B, C}: PCS rats ^{A, B, C} MHE ^{A, B} Hyperammonemic ^C	NA: Ammonia ^A	• Cerebellum ^A: ↓ Microglia and astrocyte ^A ↓ [IL-1β; TNF-α] ^A ↑ [IL-4] ^A Modulate GABA, GABA receptors and transporters ^A Modulate Glu pathway ^C • Hippocampus ^B: ↓ Microglia ↓ [IL-1β; TNF-α; IL-10] Modulate GABA and Glu receptor expression	+ Motor coordination ^A + Spatial learning and memory ^B	A: Augusti et al., 2016⁶⁶66 Agusti A, Hernández-Rabaza V, Balzano T, et al. Sildenafil reduces neuroinflammation in cerebellum, restores GABAergic tone, and improves motor in-coordination in rats with hepatic encephalopathy. CNS Neurosci Ther 2017;23(05):386–394 B: Hernandez-Rabaza et al., 2015²³23 Hernandez-Rabaza V, Agusti A, Cabrera-Pastor A, et al. Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms. J Neuroinflammation 2015;12:195 C: Erceg et al., 2005⁶⁷67 Erceg S, Monfort P, Hernández-Viadel M, Rodrigo R, Montoliu C, Felipo V. Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology 2005;41(02):299–306. Doi: 10.1002/hep.20565 https://doi.org/10.1002/hep.20565...
Tadalafil gavage	PDE-5 inhibitor	Male C57/6 mice TAA-induce ALF	↓ NO _serum	• Cerebral cortex: ↓ Microglial activation and astrocyte ↓ TNF-α, IL-1β, IL-6 ↑ BDNF, synaptophysin • Hippocampus: ↓ Microglial activation and astrocyte ↓ TNF-α, IL-1β, IL-6 Modulate Glu receptors	+ Spatial learning and memory	Franca et al.,2019⁶⁸68 França MER, Ramos RKLG, Oliveira WH, et al. Tadalafil restores long-term memory and synaptic plasticity in mice with hepatic encephalopathy. Toxicol Appl Pharmacol 2019;379:114673. Doi: 10.1016/j.taap.2019.114673 https://doi.org/10.1016/j.taap.2019.1146...
Bicuculline i.p.	GABA_A receptor antagonist	Male Wistar rats: Hyperammonemic	–	• Hippocampus: NA: Microglia activation ↓ Astrocytes activation ↓ Cell expressing IL-1β ↓ [IL-1β] Modulate Glu receptors	+ Learning index + Memory + Exploratory behavior ↓ Anxiety-like behavior	Malaguarnera, et al., 2019⁶⁹69 Malaguarnera M, Llansola M, Balzano T, et al. Bicuculline Reduces Neuroinflammation in Hippocampus and Improves Spatial Learning and Anxiety in Hyperammonemic Rats. Role of Glutamate Receptors. Front Pharmacol 2019;10:132

Drug	Kind	Model and HE type	Peripheral parameters and systemic inflammation	Central parameter and neuroinflammation	Behavioral, cognitive, and motor parameters	Reference
Cannabidiol (CBD) i.p. ^{A, B, C}	Natural compound	Female Sabra mice ^{A, B, C}: BDL ^{A, B} TAA-induce ALF ^C	↓ AST, ALT ammonia, bilirubin ^C NA: hepatic necrose ^C	↓ Astrogliosis ^C • Hippocampus: ↓ TNFRSF1A _mRNA ^A,B ↑ BDNF ^{A, B} NA: COX ^B	+ Cognitive function ^{A, B, C} + Motor function ^{A, B, C} + Neurological score ^C	A: Magen et al., 2010⁷³73 Magen I, AvrahamY, Ackerman Z, Vorobiev L,Mechoulam R, Berry EM. Cannabidiol ameliorates cognitive andmotor impairments in bile-duct ligated mice via 5-HT1A receptor activation. Br J Pharmacol 2010;159(04):950–957 B: Megan et al., 2009⁷²72 Magen I, AvrahamY, Ackerman Z, Vorobiev L,Mechoulam R, Berry EM. Cannabidiol ameliorates cognitive andmotor impairments in mice with bile duct ligation. J Hepatol 2009;51(03):528–534. Doi: 10.1016/j.jhep.2009.04.021 https://doi.org/10.1016/j.jhep.2009.04.0... C: Avraham et al., 2010⁷¹71 Avraham Y, Grigoriadis N, Poutahidis T, et al. Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice. Br J Pharmacol 2011;162(07):1650–1658
Rheum undulatum and Glycyrriza uralensis (RG) mix extract Drinking water	Herbal medicine: medicine tradicional oriental	Male Balb/C mice CCL₄-induced HE	↓ ALT, ammonia + Liver histology: ↓ inflammation, necrosis, vacuolization of hepatocytes	↓ Astrogliosis ↓MMP9 ↑ Claudin 5 ↓ TGF-β1, IL-1β _Mrna	+ Locomotor activity and distance traveled	Baek et al., 2020⁷⁴74 Baek SY, Lee EH, Oh TW, et al. Network Pharmacology-Based Approaches of Rheum undulatum Linne and Glycyrriza uralensis Fischer Imply their Regulation of Liver Failure with Hepatic Encephalopathy in Mice. Biomolecules 2020;10(03):437
Sulforaphane i.p.^{A, B}	Natural compound	Male Wistar rats: Hyperammonemic diet ^{A, B}	NA: Ammonia ^{A, B}	• Cerebellum ^B: NA: Microglia ↑ M2 macrophage ↓ Astrogliosis ↑ IL-10, IL-4 ↓ IL-1β ↓ Cell expression IL-1β Modulate GABA and GABA transporter Modulate Glu pathway • Hippocampus ^A: ↓ Microglia and astrocyte activated ↑ M2 macrophage NA: TNF-α, IL-10, IL-4 ↓ IL-6, IL-1β Modulate GABA and Glu receptors	+ Spatial learning ^A + Learning ability ^{A, B} + Motor coordination ^B	A: Hernandez-Rabaza et al., 2016⁷⁵75 Hernández-Rabaza V, Cabrera-Pastor A, Taoro-González L, et al. Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane. J Neuroinflammation 2016;13:41 B: Hernandez-Rabaza et al., 2016³⁶36 Hernandez-Rabaza V, Cabrera-Pastor A, Taoro-Gonzalez L, et al. Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia. J Neuroinflammation 2016; 13(01):83
Erythropoietin (EPO) i.p.^{A, B}	Hormone	Male Wistar rats: BDL ^{A, B}	↓ AST ^A, ↓ ALT ^B NA: Bilirubin ^{A, B} ↑ Albumin ^A NA: Albumin ^B ↑ Red blood cells ^{A, B} NA: Hemoglobin ^{A, B}	Cerebellum and hippocampus: ↓ Microglia and astrocyte ^A ↓ neuronal degeneration ^A	+ Mobility ^B + Balance function ^B + Spatial learning and memory ^B + Fear learning ^B	A: Golshani et al., 2019⁸⁰80 Golshani M, Basiri M, Shabani M, Aghaei I, Asadi-Shekaari M. Effects of erythropoietin on bile duct ligation-induced neuroinflammation in male rats. AIMS Neurosci 2019;6(02):43–53 B: Aghaei et al., 2015⁸⁷87 Aghaei I, Nazeri M, Shabani M, et al. Erythropoietin ameliorates the motor and cognitive function impairments in a rat model of hepatic cirrhosis. Metab Brain Dis 2015;30(01):197–204. Doi: 10.1007/s11011-014-9600-x https://doi.org/10.1007/s11011-014-9600-...
Fibroblast growth fator-21 (FGF-21) i.p.	Growth factor	Male C57/6J mice: TAA-induce ALF	Serum: ↓ CCL5 Liver: ↓ CCL5 ↑ IL-10 _mRNA ↓ TNF-α, IL-1β, IL-6 _mRNA ↓ TGF-β1, Hdac3, Colagen1 _mRNA ↓ Liver fibrosis	↓ CCL5 ↓ [TNF-α, IL-1β, IL-6] _mRNA ↑ [IL-10] _mRNA Modulate GABA	+ Cognitive and neurological score	Opoku et al., 2020⁸³83 Opoku YK, Liu Z, Afrifa J, et al. Fibroblast Growth Factor-21 ameliorates hepatic encephalopathy by activating the STAT3-SOCS3 pathway to inhibit activated hepatic stellate cells. EXCLI J 2020;19:567–581 Epub 2020/06/03. doi: 10.17179/excli2020-1287. PubMed PMID: 32483404; PubMed Central PMCID: PMCPMC7257252 https://doi.org/10.17179/excli2020-1287...
Taurine Gavage	Amino acid human and supplementation	Male Sprague–Dawley rats: BDL	↓ Ammonia, ALT, AST ↑Albumin	↓ Ammonia ↓ ROS, lipid peroxidation ↑GSH, antioxidant capacity	+ Motor coordination + Locomotory activity	Heidari et al., 2018⁸⁴84 Heidari R, Jamshidzadeh A, Ghanbarinejad V, Ommati MM, Niknahad H. Taurine supplementation abates cirrhosis-associated locomotor dysfunction. Clin Exp Hepatol 2018;4(02): 72–82
Fish oil Oral	Natural compounds	Male Wistar rats: TAA-induced ALF		↓SOD activity	+ Spatial memory	Staziaki et al., 2013⁷⁶76 Staziaki PV,Marques CM, Delattre AM, et al. Fish oil has beneficial effects on behavior impairment and oxidative stress in rats subjected to a hepatic encephalopathy model. CNS Neurol Disord Drug Targets 2013;12(01):84–93

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[1] Address for correspondence Eliana Cristina de Brito Toscano (email: elianacbtoscano@gmail.com).