Mitochondrial dysfunction as a mediator of hippocampal apoptosis in a model of hepatic encephalopathy

Abstract

In this study, we describe the presence of apoptosis, associated with a mitochondrial dysfunction in the hippocampus of animals in an experimental model defined as minimal hepatic encephalopathy (MHE). This experimental model was studied after 10 days of induced portal vein calibrated stricture, leading to portal hypertension and to a moderate hyperammonemia, without the presence of other evident central nervous system changes. The molecular mechanisms here proposed indicate the presence of apoptotic intrinsic pathways that point to hippocampal mitochondria as an important mediator of apoptosis in this experimental model. In this model of MHE, the presence of DNA fragmentation is documented by 2.3-times increased number of TUNEL-positive cells. These findings together with a higher ratio of the Bcl-2 family members Bax/Bcl-xL in the outer mitochondrial membrane of the MHE animals together with 11% of cytochrome c release indicate the presence of apoptosis in this experimental model. A detailed analysis of the hippocampal mitochondrial physiology was performed after mitochondrial isolation. The determination of the respiratory rate in the presence of malate plus glutamate and ADP showed a 45% decrease in respiratory control in MHE animals as compared with the sham group. A marked decrease of cytochrome oxidase (complex IV of the electron transport chain) was also observed, showing 46% less activity in hippocampal mitochondria from MHE animals. In addition, mitochondria from these animals showed less ability to maintain membrane potential (ΔΨ (m)) which was 13% lower than the sham group. Light scattering experiments showed that mitochondria from MHE animals were more sensitive to swell in the presence of increased calcium concentrations as compared with the sham group. In addition, in vitro studies performed in mitochondria from sham animals showed that mitochondrial permeability transition (MPT) could be a mitochondrial mediator of the apoptotic signaling in the presence of NH(4) (+) and calcium.

Hepatic encephalopathy: An approach to its multiple pathophysiological features

“…They also reported disturbances in the mi�� tochondrial electron transport chain in brain mitochon�� dria from rats injected with ammonia. On the other hand, in our laboratory, an opposite view in a chronic model of MHE PVL��induced cellular death was registered [58] . �e found a 5 times higher expression of the proapoptotic member of the Bcl��2 family, Bax.…”

“…The presence of DNA fragmentation with a higher ratio of the Bcl-2 family members Bax/Bcl-xL in the outer mitochondrial membrane and cytochrome c release in�� dicate the presence of apoptosis. A marked decrease of cytochrome oxidase (complex Ⅳ of the electron trans�� port chain) was also observed; mitochondria from these animals showed less ability to maintain the membrane potential �ΔΨm) stabilized [58] . Ammonia induced neuronal and oligodendroglial death, triggered apoptosis and activated caspases and cal�� pain.…”

“…Significant amounts of glutamine have been shown to be metabo�� lized in astrocytes. Thus, the generation of mitochondrial ammonia may reach high levels, inducing the mitochon�� drial potential membrane, reactive oxygen species (RO�), with the potential consequence of morpho��functional oxidative damage of the mitochondria [57,58] and its respira�� tory chain [58] .…”

“…It is also interesting that in experimental ALF, moderate hy�� pothermia prevents cerebral edema and reduces the up�� regulation of astrocytic PTBRs [133] . Central nervous system cell death cell death cell death A recent study from our laboratory has shown astrocyte death associated with mitochondrial dysfunction in hip�� pocampal CN� in an experimental model of MHE [58] . The presence of DNA fragmentation with a higher ratio of the Bcl-2 family members Bax/Bcl-xL in the outer mitochondrial membrane and cytochrome c release in�� dicate the presence of apoptosis.…”

“…The recurrent strokes are associated with vasogenic edema, as demonstrated by MR diffusion weighted imag�� ing studies, suggesting that they may be due to increased March 27, 2012|Volume 4|Issue 3| WJH|www.wjgnet.com 58 Perazzo JC et al . Hepatic encephalopathy pathophysiology � � permeability in the BBB, perhaps caused by mitochon�� drial dysfunction in the endothelium of cerebral small vessels [156] .…”