Toward an Anti-Inflammatory Strategy for Depression

It has become clear that the inflammatory immune system is altered during the course of clinical depression. In particular, studies on human patients have found depression to be associated with disturbances in the trafficking of cells of the adaptive immune system, coupled with elevations of innate immune messengers and pro-inflammatory cytokines. Paralleling these findings, stressor-based animal models of depression have implicated several cytokines, most notably interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α. Elevations of these cytokines and general inflammatory indicators, such as C-reactive protein, together with reductions of specific immune cells (e.g., T lymphocytes) might serve as useful biomarkers of depression or at least, certain subtypes of the disorder. Recent reports also suggest the possibility that anti-inflammatory agents could have therapeutic value in acting as adjunct treatments with traditional anti-depressants. Along these lines, we presently discuss the evidence for pro-inflammatory cytokine involvement in depression, as well as the possibility that anti-inflammatory agents and trophic cytokines themselves might have important anti-depressant properties

Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration

Disturbances of hippocampal plasticity, including impaired dendritic branching and reductions of neurogenesis, are provoked by stressful insults and may occur in depression. Although corticoids likely contribute to stressor-induced reductions of neurogenesis, other signaling messengers, including pro-inflammatory cytokines might also be involved. Accordingly, the present investigation assessed whether three proinflammatory cytokines, namely interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) (associated with depression) influenced cellular proliferation within the hippocampus. In this regard, systemic administration of TNF-α reduced 5-bromo-2-deoxyuridine (BrdU) labeling within the hippocampus, whereas IL-1β and IL-6 had no such effect. However, repeated but not a single intra-hippocampal infusion of IL-6 and IL-1β actually increased cellular proliferation and IL-6 infusion also enhanced microglial staining within the hippocampus. Yet, no changes in doublecortin expression were apparent, suggesting that the cytokine did not influence the birth of cells destined to become neurons. Essentially, the route of administration and chronicity of cytokine administration had a marked influence upon the nature of hippocampal alterations provoked, suggesting that cytokines may differentially regulate hippocampal plasticity in neuropsychiatric conditions

Hematopoietic cytokines as therapeutic players in early stages Parkinson’s disease

Parkinson's disease (PD) is a devastating age related neurodegenerative disease that is believed to have a lengthy prodromal state. It is critical to find methods of interfering with the progression of this early degenerative stage by inducing compensatory recovery processes to slow or prevent the eventual clinical symptoms. The current perspective article argues that immune system signalling molecules represent such a promising therapeutic approach. Two cytokines of interest are granulocyte macrophage-colony stimulating factor (GM-CSF) and erythropoietin (EPO). These hematopoietic cytokines have been protective in models of stroke, neuronal injury, and more recently PD. It is our belief that these trophic cytokines can be used not only for cell protection but also regeneration. However, success is likely dependent on early intervention. This paper will outline our perspective on the development of novel trophic recovery treatments for PD. In particular, we present new data from our lab suggesting that EPO and GM-CSF can foster neural re-innervation in a mild or partial lesion PD model that could be envisioned as reflecting the early stages of the disease

Major depressive disorder and alterations in insular cortical activity: A review of current functional magnetic imaging (fMRI) research

Major depressive disorder (MDD) is characterized by a dysregulated fronto-limbic network. The hyperactivation of limbic regions leads to increased attention and processing of emotional information, with a bias toward negative stimuli. Pathological ruminative behavior is a common symptom of depressive disorder whereby the individual is unable to disengage from internal mental processing of emotionally-salient events. In fact, lower deactivations of the neural baseline resting state may account for the increased internal self-focus. The insular cortex, with its extensive connections to fronto-limbic and association areas has recently also been implicated to be a part of this network. Given its wide-reaching connectivity, it has been putatively implicated as an integration center of autonomic, visceromotor, emotional and interoceptive information. The following paper will review recent imaging findings of altered insular function and connectivity in depressive pathology

Inflammatory Mechanisms of Neurodegeneration in Toxin-Based Models of Parkinson's Disease

Parkinson's disease (PD) has been associated with exposure to a variety of environmental agents, including pesticides, heavy metals, and organic pollutants; and inflammatory processes appear to constitute a common mechanistic link among these insults. Indeed, toxin exposure has been repeatedly demonstrated to induce the release of oxidative and inflammatory factors from immunocompetent microglia, leading to damage and death of midbrain dopamine (DA) neurons. In particular, proinflammatory cytokines such as tumor necrosis factor-α and interferon-γ, which are produced locally within the brain by microglia, have been implicated in the loss of DA neurons in toxin-based models of PD; and mounting evidence suggests a contributory role of the inflammatory enzyme, cyclooxygenase-2. Likewise, immune-activating bacterial and viral agents were reported to have neurodegenerative effects themselves and to augment the deleterious impact of chemical toxins upon DA neurons. The present paper will focus upon the evidence linking microglia and their inflammatory processes to the death of DA neurons following toxin exposure. Particular attention will be devoted to the possibility that environmental toxins can activate microglia, resulting in these cells adopting a “sensitized” state that favors the production of proinflammatory cytokines and damaging oxidative radicals

Use of induced pluripotent stem cell derived neurons engineered to express BDNF for modulation of stressor related pathology

Combined cell and gene-based therapeutic strategies offer potential in the treatment of neurodegenerative and psychiatric conditions that have been associated with structural brain disturbances. In the present investigation, we used a novel virus-free re-programming method to generate induced pluripotent stem cells (iPSCs), and then subsequently transformed these cells into neural cells which over-expressed brain derived neurotrophic factor (BDNF). Importantly, the infusion of iPSC derived neural cells (as a cell replacement and gene delivery tool) and BDNF (as a protective factor) influenced neuronal outcomes Specifically, intracerebroventricular transplantation of iPSC-derived neural progenitors that over-expressed BDNF reversed the impact of immune (lipopolysaccharide) and chronic stressor challenges upon subventricular zone adult neurogenesis and the iPSC-derived neural progenitor cells alone blunted the stressor induced corticosterone response. Moreover, our findings also indicate that mature dopamine producing neurons can also be generated using iPSC procedures and these cells appeared to be viable when infused in vivo. Taken together, these data could have important implications for using gene-plus-cell replacement methods to modulate stressor related pathology

Motor and Hippocampal Dependent Spatial Learning and Reference Memory Assessment in a Transgenic Rat Model of Alzheimer\u27s Disease with Stroke

Alzheimer\u27s disease (AD) is a debilitating neurodegenerative disease that results in neurodegeneration and memory loss. While age is a major risk factor for AD, stroke has also been implicated as a risk factor and an exacerbating factor. The co-morbidity of stroke and AD results in worsened stroke-related motor control and AD-related cognitive deficits when compared to each condition alone. To model the combined condition of stroke and AD, a novel transgenic rat model of AD, with a mutated form of amyloid precursor protein (a key protein involved in the development of AD) incorporated into its DNA, is given a small unilateral striatal stroke. For a model with the combination of both stroke and AD, behavioral tests that assess stroke-related motor control, locomotion and AD-related cognitive function must be implemented. The cylinder task involves a cost-efficient, multipurpose apparatus that assesses spontaneous forelimb motor use. In this task, a rat is placed in a cylindrical apparatus, where the rat will spontaneously rear and contact the wall of the cylinder with its forelimbs. These contacts are considered forelimb motor use and quantified during video analysis after testing. Another cost-efficient motor task implemented is the beam-walk task, which assesses forelimb control, hindlimb control and locomotion. This task involves a rat walking across a wooden beam allowing for the assessment of limb motor control through analysis of forelimb slips, hindlimb slips and falls. Assessment of learning and memory is completed with Morris water maze for this behavioral paradigm. The protocol starts with spatial learning, whereby the rat locates a stationary hidden platform. After spatial learning, the platform is removed and both short-term and long-term spatial reference memory is assessed. All three of these tasks are sensitive to behavioral differences and completed within 28 days for this model, making this paradigm time-efficient and cost-efficient

Cytokines as a stressor: Implications for depressive illness

Stressful events have been implicated in the provocation of depressive illness. Inasmuch as immunological challenge, and particularly cytokine administration, engender neuroendocrine and central neurochemical changes reminiscent of those provoked by psychogenic stressors, it was suggested that immune activation may also contribute to affective illness. The present report provides a brief overview of the neurochemical sequelae of acute and repeated interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and IL-2 treatment, describes some of the synergisms associated with these treatments, as well as their potential interactions with psychogenic stressors. In addition, a discussion is provided concerning the fact that cytokines, like stressors, may have time-dependent proactive effects, so that re-exposure to the treatments provoke greatly augmented neurochemical changes (sensitization). Given that the effects of cytokines are evident within hypothalamic, as well as extrahypothalamic sites, including various limbic regions, it is suggested that cytokines may impact on emotional changes, including depression

Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent attention has focused on lipids and their role in pro- and anti-apoptotic processes. Howeve