Temporary induction of hypoxic adaptations by preconditioning fails to enhance Schwann cell transplant survival after spinal cord injury.

Hypoxic preconditioning is protective in multiple models of injury and disease, but whether it is beneficial for cells transplanted into sites of spinal cord injury (SCI) is largely unexplored. In this study, we analyzed whether hypoxia-related preconditioning protected Schwann cells (SCs) transplanted into the contused thoracic rat spinal cord. Hypoxic preconditioning was induced in SCs prior to transplantation by exposure to either low oxygen (1% O2 ) or pharmacological agents (deferoxamine or adaptaquin). All preconditioning approaches induced hypoxic adaptations, including increased expression of HIF-1α and its target genes. These adaptations, however, were transient and resolved within 24 h of transplantation. Pharmacological preconditioning attenuated spinal cord oxidative stress and enhanced transplant vascularization, but it did not improve either transplanted cell survival or recovery of sensory or motor function. Together, these experiments show that hypoxia-related preconditioning is ineffective at augmenting either cell survival or the functional outcomes of SC-SCI transplants. They also reveal that the benefits of hypoxia-related adaptations induced by preconditioning for cell transplant therapies are not universal.

Mood and emotional disorders associated with parkinsonism, Huntington disease, and other movement disorders.

This chapter provides a review of mood, emotional disorders, and emotion processing deficits associated with diseases that cause movement disorders, including Parkinson's disease, Lewy body dementia, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia with parkinsonism, Huntington's disease, essential tremor, dystonia, and tardive dyskinesia. For each disorder, a clinical description of the common signs and symptoms, disease progression, and epidemiology is provided. Then the mood and emotional disorders associated with each of these diseases are described and discussed in terms of clinical presentation, incidence, prevalence, and alterations in quality of life. Alterations of emotion communication, such as affective speech prosody and facial emotional expression, associated with these disorders are also discussed. In addition, if applicable, deficits in gestural and lexical/verbal emotion are reviewed. Throughout the chapter, the relationships among mood and emotional disorders, alterations of emotional experiences, social communication, and quality of life, as well as treatment, are emphasized.

Hypoxia-Inducible Factor 1α (HIF-1α) Counteracts the Acute Death of Cells Transplanted into the Injured Spinal Cord.

Cellular transplantation is in clinical testing for a number of central nervous system disorders, including spinal cord injury (SCI). One challenge is acute transplanted cell death. To prevent this death, there is a need to both establish when the death occurs and develop approaches to mitigate its effects. Here, using luciferase (luc) and green fluorescent protein (GFP) expressing Schwann cell (SC) transplants in the contused thoracic rat spinal cord 7 d postinjury, we establish via in vivo bioluminescent (IVIS) imaging and stereology that cell death occurs prior to 2-3 d postimplantation. We then test an alternative approach to the current paradigm of enhancing transplant survival by including multiple factors along with the cells. To stimulate multiple cellular adaptive pathways concurrently, we activate the hypoxia-inducible factor 1α (HIF-1α) transcriptional pathway. Retroviral expression of VP16-HIF-1α in SCs increased HIF-α by 5.9-fold and its target genes implicated in oxygen transport and delivery (VEGF, 2.2-fold) and cellular metabolism (enolase, 1.7-fold). In cell death assays in vitro, HIF-1α protected cells from H2O2-induced oxidative damage. It also provided some protection against camptothecin-induced DNA damage, but not thapsigargin-induced endoplasmic reticulum stress or tunicamycin-induced unfolded protein response. Following transplantation, VP16-HIF-1α increased SC survival by 34.3%. The increase in cell survival was detectable by stereology, but not by in vivo luciferase or ex vivo GFP IVIS imaging. The results support the hypothesis that activating adaptive cellular pathways enhances transplant survival and identifies an alternative pro-survival approach that, with optimization, could be amenable to clinical translation.