Ruthenium red, mitochondrial calcium uniporter inhibitor, attenuates cognitive deficits in STZ-ICV challenged experimental animals.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cardinal features of cognitive dysfunction in an individual. Recently, the blockade of mitochondrial calcium uniporter (MCU) exhibits neuroprotective activity in experimental animals. However, the therapeutic potential of MCU has not yet been established in the management of AD. Therefore, the present study explored the therapeutic potential of either Ruthenium red (RR), a MCU blocker, or Spermine, a MCU opener, on the extent of mitochondrial calcium accumulation, function, integrity and bioenergetics in hippocampus, pre-frontal cortex and amygdale of ICV-STZ challenged rats. Experimental AD was induced in male rats by intracerebroventricular injection of streptozotocin (ICV-STZ) on day-1 (D-1) of the experimental protocol at a sub-diabetogenic dose (3 mg/kg) twice at an interval of 48 h into both rat lateral ventricles. RR attenuated ICV-STZ-induced memory-related behavioral abnormalities in Morris water maze and Y-maze tests. RR also attenuated ICV-STZ-induced decrease in the level of acetylcholine and activity of choline acetyltransferase and, increase in the activity of acetylcholinestarase in memory-sensitive rat brain regions. Further, RR attenuated mitochondrial toxicity in terms of reducing mitochondrial calcium accumulation and improving the mitochondrial function, integrity and bioenergetics in memory-sensitive brain regions of ICV-STZ challenged rats. Furthermore, RR attenuated the percentage of apoptotic cells in ICV-STZ challenged rat brain regions. However, Spermine did not alter ICV-STZ-induced behavioral, biochemical and molecular observations in any of the brain regions. These observations indicate the fact that the MCU blockage could be a potential therapeutic option in the management of sporadic type of AD.

Intracerebroventricular streptozotocin administration impairs mitochondrial calcium homeostasis and bioenergetics in memory-sensitive rat brain regions.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cardinal manifestation of cognitive dysfunction. The limitation to avail a successful drug candidate encourages researchers to establish an appropriate animal model in the novel anti-AD drug discovery process. In this context, the mechanism of mitochondrial dysfunction in cognitive deficit animals is yet to be established for intracerebroventricular injection of streptozotocin (ICV-STZ). Experimental dementia was induced in male rats by ICV-STZ on day-1 (D-1) of the experimental protocol at a sub-diabetogenic dose (3 mg/kg) twice at an interval of 48 h into both rat lateral ventricles. ICV-STZ caused cognitive decline in terms of increase in the escape latency on D-14 to D-17 and, decrease in the time spent and percentage of distance travelled in the target quadrant during Morris water maze and decrease in the spontaneous alteration behavior during Y-maze tests in rats. Further, ICV-STZ decreased the level of acetylcholine and activity of choline acetyltransferase and increased the activity of acetylcholinesterase in rat hippocampus, pre-frontal cortex and amygdala. Interestingly, ICV-STZ increased the mitochondrial calcium in addition to decrease in the mitochondrial function, integrity and bioenergetics in all rat brain regions. Further, ICV-STZ enhanced the levels of expression of NR1 subunit of N-methyl-D-aspartate receptor, mitochondrial calcium uniporter and sodium-calcium exchanger in these rat brain regions. Thus, NR1-dependent mitochondrial calcium accumulation could be considered as a major attribute to the animal model of ICV-STZ-induced AD-like manifestations. Further, drugs targeting to manage mitochondrial calcium homeostasis could best be studied in this animal model.