Liver cirrhosis represents a worldwide health problem and is a major cause of mortality. Cirrhosis is the result of extensive hepatocyte death and fibrosis induced by chronic alcohol abuse and hepatitis B and C viruses. Successful gene therapy approaches to this disease may require both reversal of fibrosis and stimulation of hepatocyte growth. Urokinase-type plasminogen activator (uPA) may serve this function, as it is an initiator of the matrix proteolysis cascade and induces hepatocyte growth factor expression. In a rat cirrhosis model, a single iv administration of a replication-deficient adenoviral vector encoding a nonsecreted form of human uPA resulted in high production of functional uPA protein in the liver. This led to induction of collagenase expression and reversal of fibrosis with concomitant hepatocyte and improved liver function. Thus, uPA gene therapy may be an effective strategy for treating cirrhosis in humans.

Adenoviral vectors efficiently target normal liver cells

No abstract

1 Nicotinylalanine, an inhibitor of kynurenine metabolism, has been shown to elevate brain levels of endogenous kynurenic acid, an excitatory amino acid receptor antagonist. This study examined the potential of nicotinylalanine to in¯uence excitotoxic damage to striatal NADPH diaphorase (NADPH-d) and g-aminobutyric acid (GABA)ergic neurones that are selectively lost in Huntington's disease. 2 A unilateral injection of the N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid, into the rat striatum produced an 88% depletion of NADPH-d neurones. Intrastriatal infusion of quinolinic acid also produced a dose-dependent reduction in striatal GABA content. 3 Nicotinylalanine (2.3, 3.2, 4.6, 6.4 nmol 5 ml 71 , i.c.v.) administered with L-kynurenine (450 mg kg 71 ), a precursor of kynurenic acid, and probenecid (200 mg kg 71 ), an inhibitor of organic acid transport, 3 h before the injection of quinolinic acid (15 nmol) produced a dose-related attenuation of the quinolinic acid-induced loss of NADPH-d neurones. Nicotinylalanine (5.6 nmol 5 ml 71 ) in combination with Lkynurenine and probenecid also attenuated quinolinic acid-induced reductions in striatal GABA content. 4 Nicotinylalanine (4.6 nmol, i.c.v.), L-kynurenine alone or L-kynurenine administered with probenecid did not attenuate quinolinic acid-induced depletion of striatal NADPH-d neurones. However, combined administration of kynurenine and probenecid did prevent quinolinic acid-induced reductions in ipsilateral striatal GABA content. 5 Injection of nicotinylalanine, at doses (4.6 nmol and 5.6 nmol i.c.v.) which attenuated quinolinic acid-induced striatal neurotoxicity, when combined with L-kynurenine and probenecid produced increases in both whole brain and striatal kynurenic acid levels. Administration of L-kynurenine and probenecid without nicotinylalanine also elevated kynurenic acid, but to a lesser extent. 6 The results of this study demonstrate that nicotinylalanine has the potential to attenuate quinolinic acid-induced striatal neurotoxicity. It is suggested that nicotinylalanine exerts its eect by increasing levels of endogenous kynurenic acid in the brain. The results of this study suggest that agents which in¯uence levels of endogenous excitatory amino acid antagonists such as kynurenic acid may be useful in preventing excitotoxic damage to neurones in the CNS.

Quinolinic acid (QUIN), a product of tryptophan metabolism by the kynurenine pathway, produces excitotoxicity by activation of NMDA receptors. Focal injections of QUIN can deplete the biochemical markers for dopaminergic, cholinergic, gabaergic, enkephalinergic and NADPH diaphorase neurons, which differ in their sensitivity to its neurotoxic action. This effect of QUIN differs from that of other NMDA receptor agonists in terms of its dependency on the afferent glutamatergic input and its sensitivity to the receptor antagonists. The enzymatic pathway yielding QUIN produces metabolites that inhibit QUIN-induced neurotoxicity. The most active of these metabolites, kynurenic acid (KYNA), blocks NMDA and non-NMDA receptor activity. Treatment with kynurenine hydroxylase and kynureinase inhibitors increases levels of endogenous KYNA in the brain and protects against QUIN-induced neurotoxicity. Other neuroprotective strategies involve reduction in QUIN synthesis from its immediate precursor, or endogenous synthesis of 7-chloro-kynurenic acid, a NMDA antagonist, from its halogenated precursor. Several other tryptophan metabolites--quinaldic acid, hydroxyquinaldic acid and picolinic acid--also inhibit excitotoxic damage but their presence in the brain is uncertain. Picolinic acid is of interest since it inhibits excitotoxic but not neuroexcitatory responses. The mechanism of its anti-excitotoxic action is unclear but might involve zinc chelation. Neurotoxic actions of QUIN are modulated by nitric oxide (NO). Treatment with inhibitors of NO synthase can augment QUIN toxicity in some models of excitotoxicity suggesting a neuroprotective potential of endogenous NO. In recent studies, certain nitroso compounds which could be NO donors, have been reported to reduce the NMDA receptor-mediated neurotoxicity. The existence of endogenous compounds which inhibit excitotoxicity provides a basis for future development of novel and effective neuroprotectants.