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 ratsA, 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- αmRNA ↑ 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. |
GABAA 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 |