Combinatorial gene therapy induces regression of hepatic encephalopathy

Abstract

Capillarization of the sinusoid impedes the clearance of neurotoxic substances in liver fibrosis. These events may result in hepatic encephalopathy. Neurological and hepatic features of rats after bile duct ligation (BDL) supplemented with Manganese (BDL+Mn 2+ ) were examined. The 4-week-old BDL rats had elevated levels of ammonia and were concomitantly fed with 1 mg ml À1 of MnCl 2 in drinking water (BDL/Mn +2 ). Five out of fifteen rats were killed and the serum, liver and brain tissue (striatum and substantia nigra) were recovered. Of the remaining BDL/Mn +2 -cirrhotic animals (n¼10), five were injected with a combination of Adenovirus-human plasminogen activator (Ad-huPA) and Adenovirus-matrix metalloproteinase-8 (Ad-MMP-8) (3Â10 11 +1.5Â10 11 vector particles per kg), and five with 4.5Â10 11 vector particles per kg of Adenovirus-b-galactosidase (Ad-b-Gal). This treatment was carried on for 10 days. The BDL/Mn +2 rats displayed tremor, rigidity and gait abnormalities, which improved notably with combinatorial gene therapy, as well as motor coordination. Liver fibrosis was evidently less after treatment with Ad-huPA+Ad-MMP-8 (25%). In the brain (striatum), Ad-huPA+Ad-MMP-8 treatment rendered higher concentrations of dopamine compared with Ad-b-Gal-treated encephalopathic rats (210 and 162 ng g À1 of tissue, respectively). The BDL/Mn +2 animals and controls treated with Ad-b-Gal showed abnormal morphology in astrocytes (gliosis) in striatum and substantia nigra, in which expressions of green fibrillar acidic protein and tyrosine hydroxylase were altered. These abnormalities decreased with Ad-huPA+Ad-MMP-8 treatment. Importantly, the latter animals showed an increment in sprouting of nervous fibers in substantia nigra. Combinatorial gene therapy improves neuroanatomical and neurochemical characteristics similar to human hepatic encephalopathy.

Function of opioidergic and dopaminergic antagonists on both spatial and object novelty detection deficits induced in rodent model of hepatic encephalopathy

“…A decrease has been observed in the DA levels in cortex, hippocampus, striatum and cerebellum along with an increase in the activity of monoamine oxidase B (MAO-B) enzyme following BDL surgery indicating alterations in the dopaminergic system [6]. In addition, BDL rats display a diminution in striatal DA concentration similar to that observed in cirrhotic patients [17]. The concentration of DA metabolite, homovanillic acid, has been shown to be increased in HE patients along with the activity of DA metabolizing enzyme MAO-A and -B as a result of chronic hyperammonemia [18].…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…A very recent study using a combinatorial gene therapy strategy (i.e., Adenovirus-MMP-8 plus Adenovirus-human plasminogen activator) proved the therapeutical effect of MMP-8 on liver fibrosis regression, demonstrating that MMP-8 gene insertion improves neuroanatomical and neurochemical conditions in hepatic encephalopathy (Galvez-Gastelum et al, 2011).…”

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

“…As the first study reported the reduction in TH-IR SNc neurons after porto-caval anastomosis onto rats, an alternative model of HE, in 1991, to date, a few studies have described the neurotoxic effects of HE on the nigrostriatal DA-ergic neurons in vivo ( Cauli et al., 2009 ; El Hiba et al., 2016 ). Among these, a recent study that aimed to reveal the therapeutic action of combinatorial delivery of genes, namely, human plasminogen activator and matrix metalloproteinase-8, used nigrostriatal DA-ergic neurons as the regional target for gene delivery ( Gálvez-Gastélum et al., 2010 ). A few studies in vitro also have shown that DA-ergic neurons are preferentially affected by glutamate toxicity ( Kikuchi and Kim, 1993 ; Casper et al., 2000 ).…”