Preclinical Models of Hepatic Encephalopathy

Anthony S. Basile1, Kevin Mullen2

1 Laboratory of Bio‐Organic Chemistry, National Institute of Diabetes and Digestive & Kidney Diseases, NIH, Bethesda, Maryland, 2 Case Western Reserve University, Cleveland, Ohio
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.3
DOI:  10.1002/0471142301.ns0903s08
Online Posting Date:  May, 2001
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Parkinson's disease is a neurodegenerative disease in which pigmented midbrain neurons progressively die producing a dopamine (DA) deficit in the striatum which manifests as an akinetic movement disorder. Experimentally induced striatal DA depletion in animals is a valid model of parkinsonism. The capacity of certain substances to damage catecholaminergic neurones has been used for a long time to produce DA deficiency in animals. This unit focuses on methods for inducing parkinsonism using the neurotoxins MPTP and 6‐hydroxy dopamine and methods for evaluating the animals. Other models are briefly reviewed.

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Table of Contents

  • Basic Protocol 1: Encephalopathy Associated with Hepatotoxin‐Induced Acute Hepatic Failure: The Galactosamine‐Treated Rabbit
  • Basic Protocol 2: Encephalopathy Associated with Hepatotoxin‐Induced Acute Hepatic Failure: The Thioacetamide‐Treated Rat
  • Basic Protocol 3: Encephalopathy Associated with Surgically Induced Acute Hepatic Failure: Ligation of Rat Hepatic Arteries
  • Basic Protocol 4: Encephalopathy Associated with Hepatotoxin‐Induced Chronic Hepatic Failure: The Carbon Tetrachloride‐Treated Rat
  • Basic Protocol 5: Encephalopathy Associated with Surgically Induced Portacaval Shunting: Rats with Sutured Portacaval Shunts
  • Alternate Protocol 1: Encephalopathy Associated with Surgically Induced Portacaval Shunting: Rats with Nonsutured (or Button) Portacaval Shunts
  • Reagents and Solutions
  • Commentary
  • Figures
  • Tables
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Basic Protocol 1: Encephalopathy Associated with Hepatotoxin‐Induced Acute Hepatic Failure: The Galactosamine‐Treated Rabbit

  • 2‐kg male New Zealand White rabbits, 8 to 10 weeks old (e.g., Charles Rivers Laboratories)
  • GalN solution (see recipe)
  • Rabbit restrainer (Stoelting)
  • 10‐ml syringe
  • 25‐G butterfly infusion kit (Vacutainer; Becton Dickinson)
  • Alcohol wipes
  • Small artery clamp (Dieffenbach serrefine, Roboz Surgical Instruments)

Basic Protocol 2: Encephalopathy Associated with Hepatotoxin‐Induced Acute Hepatic Failure: The Thioacetamide‐Treated Rat

  • Male Sprague‐Dawley rats, 200 to 250 g (e.g., Taconic Farms)
  • TAA solution (see recipe)
  • Dextrose/electrolyte solution (see recipe)
  • 0.9% (w/v) NaCl solution
  • 1‐ and 20‐ml syringes
  • 20‐ and 22‐G needles
  • Rectal thermometer
  • Heat lamp or heating pad

Basic Protocol 3: Encephalopathy Associated with Surgically Induced Acute Hepatic Failure: Ligation of Rat Hepatic Arteries

  • Male Sprague‐Dawley rats, 250 g (e.g., Taconic Farms)
  • Nitrous oxide (Matheson Gas Products)
  • Oxygen (Matheson Gas Products)
  • Methoxyflurane (Schering)
  • Topical iodine disinfectant solution
  • Sterile saline: 0.9% (w/v) NaCl, 37°C
  • 5% (w/v) dextrose in sterile saline
  • Penicillin G
  • Veterinary gaseous anesthesia delivery instrument (Stoelting)
  • Hair clipper (Roboz Surgical Instruments)
  • Procedure board
  • 4.5‐in. (11.4‐cm) fine thumb dressing forceps (Roboz Surgical Instruments)
  • 4.5‐in. (11.4‐cm) sharp/blunt straight operating scissors (Roboz Surgical Instruments)
  • Fomon retractors (optional; Fine Science Tools)
  • 4 × 4–in., 8‐ply gauze sponges
  • 4‐in. (10‐cm) serrated microdissection forceps, curved and straight (Roboz Surgical Instruments)
  • 3‐0 and 4‐0 silk sutures
  • Curved anastomosis clamp: fashion from a 1.5‐in. (3.8‐cm) Dieffenbach serrefine clamp (Roboz Surgical Instruments) by grinding out the jaws to resemble a Satinski clamp (Funovics et al., )
  • 1‐ to 2‐mm microvascular clip and 4.75‐in. (11.4‐cm) microclip setting forceps (Roboz Surgical Instruments)
  • 4.5‐in. (11.4‐cm) angled microdissection scissors (Roboz Surgical Instruments)
  • 3.4‐in. (8.6‐cm) straight DeBakey atraumatic bulldog clamp (Roboz, Surgical Instruments)
  • 7‐0 monofilament sutures with swaged needles
  • 5.75‐in. (14.6‐cm) extra delicate, straight, Castroviejo needle holders with catch (Roboz Surgical Instruments)
  • Angled vessel dilator with 0.3‐mm tips (optional; Fine Science Tools)
  • Cutting needle, size 4
  • 4.75‐in. (11.4‐cm) extra delicate Olsen‐Hegar needle holder (Roboz Surgical Instruments)
  • 9‐mm Autoclips and applier (Roboz Surgical Instruments)
  • 3‐in. (7.6‐cm), 10‐mm blade, curved Castroviejo microdissection spring scissors (Roboz Surgical Instruments)
  • 1‐, 3‐, and 12‐ml syringes
  • 25‐G needles

Basic Protocol 4: Encephalopathy Associated with Hepatotoxin‐Induced Chronic Hepatic Failure: The Carbon Tetrachloride‐Treated Rat

  • Male Wistar rats, 150 to 200 g (e.g., Taconic Farms)
  • Sodium phenobarbital (Sigma)
  • CCl 4 (Aldrich)
  • Methoxyflurane (Schering)
  • Oxygen
  • Veterinary gaseous anesthesia delivery instrument (Stoelting)
  • 16‐ to 18‐G curved feeding tubes with rounded tip (Roboz Surgical Instruments) attached to:
  •  Repeating pipettor (e.g., Eppendorf) with 25‐ml Combitip cartridge (Brinkmann), or
  •  12‐ml syringe
  • Animal balance with 1‐g accuracy over the range of 200 to 500 g

Basic Protocol 5: Encephalopathy Associated with Surgically Induced Portacaval Shunting: Rats with Sutured Portacaval Shunts

  • 14‐G standard‐wall Teflon tubing (Small Parts)
  • 7‐mm, ⅜‐circle taper needle
  • Toothed mosquito hemostat (Roboz Scientific Instruments)
  • 1.5‐in. (3.8‐cm) curved Dieffenbach serrefine clamp (Roboz Surgical Instruments)
  • Straight and curved anatomical forceps
  • Additional reagents and equipment for preparing anastomosis buttons (Funovics et al., ; van Dongen et al., )
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Literature Cited

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Key References
  Basile, 1996. See above.
  Recent review of neurotransmitter changes in humans with liver failure and several popular animal models of hepatic encephalopathy
   Mullen, K.D., Birgisson, S., Ga, R.C., and Conjeevaran, H. 1994. Animal models of hepatic encephalopathy and hyperammonemia. In Hepatic Encephalopathy, Hyperammonemia and Ammonia Toxicity (V. Felipo and S. Grisolia, eds.) pp. 1‐10. Plenum Press, New York.
  Codifies the problems associated with the application of several models of liver failure to the study of hepatic encephalopathy.
   Mullen and Dasarathy, 1999. See above.
  Good review of the characteristics of hepatic encephalopathy in humans, along with the criteria for a more accurate system for characterizing and staging hepatic encephalopathy.
  van Dongen, 1990. See above.
  Excellent source of surgical techniques necessary for the production of PCS and HAL rats.
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