Influence of albumin dialysis (MARS) on neuronal network activity in vitro - early results

Introduction

In liver failure, toxic substances accumulate in the body that may disturb the function of the central nervous system. This is generally thought to be the cause of hepatic encephalopathy and coma. A new dialysis treatment based on albumin dialysis (Molecular Adsorbents Re-circulating-System, MARS) was developed to remove accumulating toxins from patients in liver failure [1]. Clinical studies have shown that MARS treatments can ameliorate hepatic encephalopathy of patients in severe liver failure [2].

The mechanisms how accumulating substances may lead to cerebral dysfunctions and hepatic coma are not clearly understood, primarily because of the difficulty of obtaining conclusive evidence from in vivo models. Furthermore, the degree of hepatic encephalopathy does not always correlate with plasma concentrations of potential toxins. Spontaneously electrically active neuronal networks cultured on microelectrode plates may be a means to study the effects of potential toxins on neuronal function under defined conditions in vitro. Previous work has demonstrated the specificity and reversibility of network responses to neurotransmitters and a variety of neuroactive compounds. We investigated the reaction of these networks to ultrafiltrates of human blood plasma to determine if toxins in liver failure can be detected with this system, and if so, to evaluate the effect of MARS treatments on the network responses. Hypotheses: 1) There is a difference between neuronal responses to normal human plasma and plasma from patients in hepatic coma. 2) MARS treatments diminish effects of patient samples on neuronal activity.

References

• 1 Stange J, Mitzner S, Ramlow W, Gliesche T, Hickstein H, Schmidt R. A new procedure for the removal of protein bound drugs and toxins.  ASAIO Journal. (1993);  39 M621-M625
• 2 Stange J, Mitzner S R, Risler T, Erley C M, Lauchart W, Goehl H, Klammt S, Peszynski P, Freytag J, Hickstein H, Löhr M, Liebe S, Schareck W, Hopt U T, Schmidt R. Molecular Adsorbent Recirculating System (MARS): Clinical results of a new membrane-based blood purification system for bioartificial liver support.  Artificial Organs. (1999);  23 319-330
• 3 Gross G W. Internal dynamics of randomized mammalian neuronal networks in culture. Stenger DA and McKenna TM Enabling Technologies for Cultured Neural Networks Academic Press, New York 1994: pp 277-317.
• 4 Gross G W, Norton S, Gopal K, Schiffmann D, Gramowski A :. Neuronal networks in vitro: Applications to neurotoxicology, drug development, and biosensors.  Biosensors and Bioelectronics. (1997);  10 553-567
• 5 Butterworth R F. Complications of cirrhosis III. Hepatic encephalopathy.  J. Hepatol. (2000);  32 (1 Suppl) 171-180
• 6 Plum F. Handbook of Clinical Neurology. Vinken PJ New York; American Elsevier 1969 Vol. 27: 349-377.
• 7 Hazell A S, Butterworth R F. Hepatic encephalopathy: an update of pathophysiologic mechanisms.  Proc. Soc. Exp. Biol. Med. (1999);  222 99-112
• 8 Albrecht J, Jones E A. Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome.  J. Neurol. Sci. (1999);  170 138-146
• 9 Jones E A, Basile A S. Does ammonia contribute to increased GABA-ergic neurotransmission in liver failure?.  Metab. Brain Dis. (1998);  13 351-360