Mitochondrial Deficits Accompany Cognitive Decline Following Single Bilateral Intracerebroventricular Streptozotocin.

BACKGROUND: Bilateral intracerebroventricular (ICV) administration of streptozotocin (STZ) causes Alzheimer's disease (AD)-type neurodegeneration in rats. The model is increasingly used for investigating pathology and therapeutic strategies for AD. OBJECTIVE: The present study investigated cognitive abilities in rats infused with STZ-ICV in relation to hippocampal and cortical mitochondrial functions during a period of 60 days. METHODS: Cognitive functions were assayed in rats employing various mazes. Mitochondrial state-3-respiration, complex-I activity and dynamin related protein-1 (DRP-1) expression were measured respectively by oxygraph, spectrophotometry and immunoblot assay. Amyloidosis was investigated employing Congo red staining. RESULTS: One-time ICV-STZ infused animals exhibited body-weight loss and impaired cognitive ability from 14(th) day post-infusion. A significant loss of mitochondrial electron transport chain complex-I activity in the hippocampi and cortices was found by 14 days, and persisted up to 60 days following ICV-STZ infusion. Mitochondrial state-3 respiration was unaltered in these brain regions by 14 days, but significantly decreased from 21 days after STZ administration. DRP-1 expression was significantly increased in the hippocampi and cortices of these animals 21 days after infusion, but persisted only in the hippocampi up to 60 days. Congophilic granules indicative of amyloidosis were detected in the hippocampus by 21 days. CONCLUSION: Our results suggest that the non-genetic sporadic AD (sAD) rat model developed by single-time STZ-ICV infusion exhibits protein aggregation and dementia probably resulting from increased mitochondrial fragmentation and functional aberrations. The present study reinforces the validity of this model for studying pathogenesis and potential therapies of sAD.

Regenerative therapy in experimental parkinsonism: mixed population of differentiated mouse embryonic stem cells, rather than magnetically sorted and enriched dopaminergic cells provide neuroprotection.

AIM: The objective of the study was to develop regenerative therapy by transplanting varied populations of dopaminergic neurons, differentiated from mouse embryonic stem cells (mES) in the striatum for correcting experimental parkinsonism in rats. METHODS: mES differentiated by default for 7 days in serum-free media (7D), or by enhanced differentiation of 7D in retinoic acid (7R), or dopaminergic neurons enriched by manual magnetic sorting from 7D (SSEA-) were characterized and transplanted in the ipsilateral striatum of 6-hydroxydopamine-induced hemiparkinsonian rats. Neurochemical, neuronal, glial and neurobehavioral recoveries were examined. RESULTS: 7R and SSEA- contained significantly reduced NANOG and high MAP2 mRNA and protein levels as revealed, respectively, by reverse transcriptase-PCR and immunocytochemistry, compared with 7D. Striatal engraftment of 7D resulted in a significantly better behavioral and neurochemical recovery, as compared to the animals that received either 7R or SSEA-. The 7R transplanted animals showed improvement neither in behavior nor in striatal dopamine level. The grafted striatum revealed increased GFAP staining intensity in 7D and SSEA-, but not in 7R cells transplanted group, suggesting a vital role played by glial cells in the recovery. Substantia nigra ipsilateral to the side of the striatum, which received transplants showed more tyrosine hydroxylase immunostained neurons, as compared to 6-hydroxydopamine-infused animals. CONCLUSION: These results demonstrate that default differentiated mixed population of cells are better than sorted, enriched dopaminergic cells, or cells containing more mature neurons for transplantation recovery in hemiparkinsonian rats.