Hypoxically preconditioned-bone marrow stromal cells attenuate post-stroke depression Open Access

Winter, Megan M. (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/rb68xc68r?locale=en


Ischemic stroke is the leading cause of long-term disability in the U.S., in part because of the debilitating post-stroke depression (PSD) that affects approximately one-third of stroke survivors. PSD leaves stroke survivors at a greater chance of increased disability, delayed functional recovery, decreased cognitive function, morbidity, and mortality. Due to the detrimental effects associated with PSD, it is necessary that new and innovative treatments for PSD are investigated in order to improve long-term patient outcomes. Here we will explore the use of hypoxically preconditioned-bone marrow stromal cells (HP-BMSCs) as a novel treatment for PSD. BMSCs are known to confer a number of benefits including enhanced cell migration to the site of injury, improved functional outcomes, and enhanced neurotrophic support, and we have previously shown that hypoxic-preconditioning increases oxytocin and oxytocin receptor expression in vivo. Oxytocin, a hormone secreted by the posterior lobe of the pituitary gland, is known to induce and facilitate social behaviors and is believed to be a psychosocial mediator of stroke outcome. Thus, treatment with HP-BMSCs may be especially beneficial for stroke survivors who commonly experience social impairment following stroke. The results of this investigation confirm our predictions, that treatment with HP-BMSCs, as a result of their influence on oxytocin levels, attenuate the depressive-like phenotype found in our stroke animals post-stroke, and restore sociability to levels similar to controls.

Table of Contents

Chapter I. Background: Post-stroke depression: 1

A. Symptoms: 1

B. Prevalence: 2

C. Risk factors: 3

D. Early Predictors: 4

E. Assessment and Diagnosis: 4

1. Beck Hopelessness Scale: 6

2. Beck Depression Inventory: 7

3. Barthel Index Score: 7

4. Center for Epidemiologic Studies Depression Scale: 7

5. Geriatric Depression Scale: 8

6. Hamilton Depression Rating Scale: 8

7. Hospital Anxiety and Depression Scale: 9

8. Mini-Mental State Examination: 9

9. Montgomery-Asberg Depression Rating Scale: 9

10. Patient-Health Questionnaire: 10

11. Present State Examination: 10

12. Post-stroke Depression Scale: 10

13. Zung Self-rating Depression Scale: 11

F. Underdiagnosis: 11

G. Treatment: 12

1. Psychotherapy: 12

2. Pharmaceuticals: 13

2.1 Nortriptyline: 13

2.2 Citalopram: 14

2.3 Fluoxetine: 14

2.4 Sertraline: 15

2.5 Venlafaxine: 16

2.6 Mirtazapine: 17

H. Influence on Recovery: 17

I. Hypothesized Mechanisms: 20

1. Biological Hypothesis: 20

1.1 Biogenic Amine Hypothesis: 20

1.2 Cytokine Hypothesis: 22

1.3 Gene Polymorphism Hypothesis: 23

1.4 Neurogenesis Hypothesis: 23

2. Psychological Hypothesis: 24

J. Animal Models: 25

1. Middle Cerebral Artery Occlusion: 25

2. MCAO + Chronic Mild Stress: 26

3. MCAO+ Social Isolation: 26

4. MCAO + Spatial Restrain Stress: 27

K. Behavioral Tasks Use to Assess PSD in Animal Models: 27

1. Forced Swim Test: 28

2. Tail Suspension Test: 29

3. Sucrose Preference Test: 29

4. Splash Test: 30

5. Novelty-Suppressed Feeding: 30

6. Social Interaction Test: 31

L. Conclusion: 31

Chapter II. HP-BMSC treatment for PSD: 32

A. Introduction: 32

B. Methods: 34

C. Results: 40

D. Discussion: 44

E. Summary and Future Directions: 49

F. Figures: 50

Chapter III: References: 56

Appendix: Diffuse Axonal Injury in Traumatic Brain Injury and the Potential for Remyelination Through Stem Cell Therapy

A. Introduction: A1

B. Injury Biomechanics and Pathophysiology of Diffuse Axonal Injury: A2

C. Pathology of DAI: A3

D. Diagnosis of Axonal Damage after DAI: A4

1. Clinical Diagnosis: A4

2. Post-mortem Diagnosis: A5

E. Myelin Degeneration after DAI: A6

F. Oligodendrocytes in DAI: A7

G. Endogenous Oligodendrogenesis after Brain Injury: A8

H. Regulation of neurite outgrowth and neuritogenesis: A8

I. Cellular Therapy and Preconditioning Strategy of Transplanted Cells: A11

J. Stem Cell Derived Oligodendrogenesis: A12

K. Neurotrophic Factors Provide Trophic Support to Endogenous Neural Stem Cells: A14

L. Conclusion: A15

M. References: A17

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