Prevention of cell damage in ischaemia: novel molecular targets in mitochondria

Abstract

Ischaemia results in a decrease of blood supply to an organ. It may be sudden or progressive, partial or complete. In any case, the lack of oxygen induces a decrease in ATP generation followed by a reduction of cellular energy-dependent processes. When ischaemia is followed by a reperfusion, the efflux of oxygen in an anoxied organ promotes an excess of reactive oxygen species (ROS) generation, which impairs the restoration of ATP synthesis. Both effects induce cellular alterations that can lead to cell death in both necrotic and apoptotic forms. As ATP synthesis and ROS generation both occur in mitochondria, they are obvious targets for pharmacological interventions aiming to prevent or block deleterious effects induced by a lack of oxygen. Different approaches may be used according to the state of the pathological process under investigation. In general, prevention of the ischaemic process is more successful than the cure of the following reperfusion state. This review summarises pharmacological strategies designed to improve cellular protection before or during ischaemia-reperfusion acting via the mitochondria and highlights promising new mitochondrial targets to be considered for future therapies.

Mechanism underlying mitochondrial protection of asiatic acid against hepatotoxicity in mice

“…Our data have revealed that AA could act on mitochondria PTP directly against Ca 2+ -induced mitochondrial swelling, membrane potential rupture and release of matrix Ca 2+ , which suggests that AA could protect mitochondria against liver injury induced by LPS + D-GalN. Indeed, it has been believed that inhibition of mitochondrial PTP opening might constitute a relevant pharmacological approach to protect cells from death, and the search for novel PTP inhibitors should be an important strategy for the treatment of liver diseases (Morin et al 2002;Elimadi et al 2003).…”

The Effects of Difumarate Salt S-15176 after Spinal Cord Injury in Rats

“…It has been suggested that cyclosporine shows neuroprotective effects by inhibiting mitochondrial membrane permeability, it has also been reported that it could be important for preventing cell death in experimental traumatic cord injury studies 13 14) . Morin et al 38) have reported that search for novel PTP inhibitors should be considered with great interest, for molecules which can inhibit PTP opening can provide protection against reperfusion injury.…”

“…It has been demonstrated that S-15176 inhibits Adenine Nucleotide Translocase which regulates ADP/ATP exchange on mitochondrial membrane and is able to prevent PTP opening also in this way 1) . Morin et al 38) have shown that S-15176 inhibits the mtPTP induced by not only Ca(2+) and inorganic phosphate, but also by tert-butylhydroperoxide or phenylarsine oxide. In a recent study S-15176 has been proposed to be a more universal permeability transition inhibitor than Cyclosporine A or oligomycin as S-15176 was effective in suppressing the permeability transition and the subsequent cyt-c release induced by Ag(+) 30) .…”

“…This protective effect has been associated with the preservation of mitochondrial function and seemed to be related to the inhibition of mitochondrial permeability transition pore (mPTP) opening 16) S-15176 was able to inhibit ATP synthase activity and to stimulate the hydrolytic activity of the enzyme without relation to its permeability transition pore (PTP) inhibiting property. On this account it has been proposed that S-15176 interacts with several targets in mitochondria 38) . S-15176 was suggested to prevent both mitochondrial swelling and cyt-c release and maintain MMP 41) .…”

Hepatoprotection through regulation of voltage dependent anion channel expression by Amomum subulatum Roxb seeds extract

“…Indeed, it has been believed that inhibition of mitochondrial PTP opening might constitute a relevant pharmacological approach to protect cells from death and the search for novel PTP inhibitors should be an important strategy for the treatment of liver diseases. [ 22 23 ]…”