Neuroprotective Effect of Nortriptyline in Overt Hepatic Encephalopathy Through Attenuation of Mitochondrial Dysfunction.

Abstract

Hyperammonemia associated with overt hepatic encephalopathy (OHE) causes excitotoxic neuronal death through activation of the cytochrome C (CytC)-mediated mitochondria-dependent apoptotic pathway. We tested the therapeutic effect of nortriptyline (NT), a mitochondrial permeability transition pore (mPTP) blocker that can possibly inhibit mitochondrial CytC efflux to the cytosol on in vivo and in vitro OHE models. After ensuring the generation of OHE rats, established by bile duct ligation (BDL), they were intraperitoneally administered either 20 mg/kg NT (i.e., BDL+NT) or another vehicle (i.e., BDL+VEH) for 14 days. Compared with the control, BDL+VEH showed an increment of motor deficits, cell death, synaptic loss, apoptosis, and mitochondria with aberrant morphology in substantia nigra compacta dopaminergic (DA-ergic) neurons. However, the extent was significantly reversed in BDL+NT. Subsequently, we studied the neuroprotective mechanism of NT using PC-12 cells, a DA-ergic cell line, which exposed glutamate used as an excitotoxin. Compared with the control, the cells exposed to 15 mM glutamate (i.e., GLU) showed incremental cell death, apoptosis, and demise in mitochondrial respiration. Importantly, efflux of CytC from mitochondria to cytosol and the dissipation of mitochondrial membrane potential (△Ψm), an indicator of mPTP opening, were prominent in GLU. However, compared with the GLU, the cells cotreated with 10 μM NT (i.e., GLU+NT) showed a significant reduction in the aforementioned phenomenon. Together, we concluded that NT can be used for OHE therapeutics, mitigating the excitotoxic death of substantia nigra compacta DA-ergic neurons via mPTP-associated mitochondrial dysfunction inhibition.

• Authors: Ji Heun Jeong, Do Kyung Kim, Nam-Seob Lee, Young-Gil Jeong, Ho Won Kim, Jong-Seok Kim, Seung-Yun Han
• Journal: ASN neuro (ASN Neuro) 2018 Jan-Dec Vol. 10 Pg. 1759091418810583 ISSN: 1759-0914 [Electronic] United States
• PMID: 30428281 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neuroprotective Agents
• Glutamic Acid
• Nortriptyline

Topics

• Animals
• Apoptosis (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Exploratory Behavior (drug effects)
• Glutamic Acid (pharmacology)
• Hepatic Encephalopathy (complications, drug therapy, pathology)
• In Situ Nick-End Labeling
• Liver Function Tests
• Male
• Maze Learning (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Microscopy, Electron, Transmission
• Mitochondria (drug effects, ultrastructure)
• Motor Activity (drug effects)
• Neuroprotective Agents (therapeutic use)
• Nortriptyline (therapeutic use)
• Oxygen Consumption (drug effects)
• PC12 Cells (drug effects)
• Rats
• Rats, Sprague-Dawley