Using mitochondrial respiration inhibitors to design a novel model of bipolar disorder-like phenotype with construct, face and predictive validity.

We mimicked mild mitochondrial-distress robustly reported in bipolar-disorder (BD) by chronic exposure to uniquely low doses of inhibitors of mitochondrial-respiration complexes in vitro and in vivo. Exposure of the neuronal-originating SH-SY5Y cells to very low dose (10 pM) rotenone, a mitochondrial-respiration complex (Co)I inhibitor, for 72 or 96 h did not affect cell viability and reactive oxygen species (ROS) levels. Yet, it induced a dual effect on mitochondrial-respiration: overshooting statistically significant several-fold increase of most oxygen-consumption-rate (OCR) parameters vs. significantly decreased all OCR parameters, respectively. Chronic low doses of 3-nitropropionic acid (3-NP) (CoII inhibitor) did not induce long-lasting changes in the cells' mitochondria-related parameters. Intraperitoneal administration of 0.75 mg/kg/day rotenone to male mice for 4 or 8 weeks did not affect spontaneous and motor activity, caused behaviors associated with mania and depression following 4 and 8 weeks, respectively, accompanied by relevant changes in mitochondrial basal OCR and in levels of mitochondrial-respiration proteins. Our model is among the very few BD-like animal models exhibiting construct (mild mitochondrial dysfunction), face (decreased/increased immobility time in the forced-swim test, increased/decreased consumption of sweet solution, increased/decreased time spent in the open arms of the elevated plus maze) and predictive (reversal of rotenone-induced behavioral changes by lithium treatment) validity. Our rotenone regime, employing doses that, to the best of our knowledge, have never been used before, differs from those inducing Parkinson's-like models by not affecting ROS-levels and cell-viability in vitro nor motor activity in vivo.

Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington's disease.

Huntington's disease (HD) is a hereditary, progressive and ultimately fatal neurodegenerative disorder. Excitotoxicity and reduced availability of neurotrophic factors (NTFs) likely play roles in HD pathogenesis. Recently we developed a protocol that induces adult human bone marrow derived mesenchymal stem cells (MSCs) into becoming NTF secreting cells (NTF(+) cells). Striatal transplantation of such cells represents a promising autologous therapeutic approach whereby NTFs are delivered to damaged areas. Here, the efficacy of NTF(+) cells was evaluated using the quinolinic acid (QA) rat model for excitotoxicity. We show that NTF(+) cells transplanted into rat brains after QA injection survive transplantation (19% after 6 weeks), maintain their NTF secreting phenotype and significantly reduce striatal volume changes associated with QA lesions. Moreover, QA-injected rats treated with NTF(+) cells exhibit improved behavior; namely, perform 80% fewer apomorphine induced rotations than PBS-treated QA-injected rats. Importantly, we found that MSCs derived from HD patients can be induced to become NTF(+) cells and exert efficacious effects similarly to NTF(+) cells derived from healthy donors. To our knowledge, this is the first study to take adult bone marrow derived mesenchymal stem cells from patients with an inherited disease, transplant them into an animal model and evidence therapeutic benefit. Using MRI we demonstrate in vivo that PBS-treated QA-injected striatae exhibit increasing T(2) values over time in lesioned regions, whereas T(2) values decrease in equivalent regions of QA-injected rats treated with NTF(+) cells. We conclude that NTF cellular treatment could serve as a novel therapy for managing HD.