Marta Nowacka

Vascular endothelial growth factor (VEGF) and its role in the central nervous system: A new element in the neurotrophic hypothesis of antidepressant drug action

Vascular endothelial growth factor (VEGF) is a well-known cellular mitogen, and a vascular growth factor and permeability regulator. It participates in physiological and pathological processes of angiogenesis and in the development of lymphatic vessels. In addition to the proangiogenic activity, studies of recent years have revealed neurotrophic and neuroprotective potential of VEGF both in the peripheral and central nervous system. VEGF directly influences Schwann cells, neuronal progenitor cells, astrocytes and microglia. This factor plays an import role in developmental processes of the nervous tissue since it is implicated in neurogenesis and the regulation of neuronal development, and in the differentiation and formation of vessels in the brain. VEGF elicits its biological effect via an interaction with three VEGF receptor subtypes: VEGFR1, VEGFR2 and VEGFR3. In the nervous system, VEGFR2 signaling prevails. VEGF as a trophic factor, influencing both vascular endothelial cells and brain cells is a focus of the studies on neuropsychiatric disorders and psychotropic drug action. Antidepressant drugs were shown to induce hippocampal expression of VEGF. In addition, the experiments in animals models of depression have demonstrated that VEGFR2 signaling is indispensable for cellular and behavioral response to antidepressant drugs. Acquiring a deeper knowledge into the signaling pathways engaged in neurogenic and behavioral VEGF actions can unravel new targets for more efficient and quick acting antidepressant drugs.

BDNF and VEGF in the pathogenesis of stress-induced affective diseases: An insight from experimental studies

Stress is known to play an important role in etiology, development and progression of affective diseases. Especially, chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal axis (HPA), neurotransmission and the immune system, acts as a trigger for affective diseases. It has been reported that the rise in the concentration of pro-inflammatory cytokines and persistent up-regulation of glucocorticoid expression in the brain and periphery increases the excitotoxic effect on CA3 pyramidal neurons in the hippocampus resulting in dendritic atrophy, apoptosis of neurons and possibly inhibition of neurogenesis in adult brain. Stress was observed to disrupt neuroplasticity in the brain, and growing evidence demonstrates its role in the pathomechanism of affective disorders. Experimental studies indicate that a well-known brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) which have recently focused increasing attention of neuroscientists, promote cell survival, positively modulate neuroplasticity and hippocampal neurogenesis. In this paper, we review the alterations in BDNF and VEGF pathways induced by chronic and acute stress, and their relationships with HPA axis activity. Moreover, behavioral effects evoked in rodents by both above-mentioned factors and the effects consequent to their deficit are presented. Biochemical as well as behavioral findings suggest that BDNF and VEGF play an important role as components of cascade of changes in the pathomechanism of stress-induced affective diseases. Further studies on the mechanisms regulating their expression in stress conditions are needed to better understand the significance of trophic hypothesis of stress-induced affective diseases.

Chronic social instability stress enhances vulnerability of BDNF response to LPS in the limbic structures of female rats: a protective role of antidepressants.

The aim of the present study was to estimate the influence of antidepressants given chronically on brain-derived neurotrophic factor (BDNF) alterations induced by lipopolysaccharide (LPS) in the amygdala and hippocampus of female rats subjected to chronic social instability stress (CSIS) for 29-30 days. CSIS was used as a paradigm known to be more stressful for females because stress induces affective disorders more frequently in women than men. An increased relative adrenal weight and a tendency towards the enhanced plasma corticosterone concentration were found in the stressed rats. Sucrose preference was not changed. On the last experimental day, the rats in the estrus phase were injected ip with LPS (1mg/kg). In the stressed rats, LPS administration decreased BDNF mRNA levels in both limbic structures. Desipramine (10mg/kg), fluoxetine (5mg/kg) or tianeptine (10mg/kg) given ip once daily reversed the effect of the combined stress and LPS, and tianeptine induced the strongest effects. These results indicate that chronic stress enhances vulnerability of BDNF response to deleterious influence of neuroinflammation in the examined limbic structures, what may account for its role in triggering neuropsychiatric diseases. The observed effect of antidepressants may be of significance for their therapeutic effects in the stress-induced affective disorders in females.

Different influence of antipsychotics on the balance between pro- and anti-inflammatory cytokines depends on glia activation: An in vitro study

HighlightsThe study estimated the effect of antipsychotics on IL‐1&bgr;, TNF‐&agr; and IL‐10 expression.Study was made on the unstimulated and LPS‐stimulated rat primary glial cultures.The effect of antipsychotics on cytokine expression depended on glia activation.In the unstimulated cultures, antipsychotics markedly increased IL‐10 expression.Not all drugs induced antiinflammatory effect under strong inflammatory activation. ABSTRACT The microglial hypothesis of schizophrenia suggests that its neuropathology is closely associated with neuroinflammation manifested, inter alia, by an increased expression of cytokines. However, clinical investigations imply that schizophrenia is a heterogeneous disease and in some groups of patients the activated inflammatory process does not contribute to the disease‐associated impairment of brain function. Clinical studies revealed also an equivocal impact of antipsychotics on peripheral and CSF cytokines, whereas experimental research performed on the stimulated glia cultures showed their inhibitory effect on pro‐inflammatory cytokine levels. In the present study, the effect of chlorpromazine, haloperidol and risperidone (0.5, 5 or 10 &mgr;M) on production of pro‐inflammatory cytokines IL‐1&bgr; and TNF‐&agr; and anti‐inflammatory IL‐10 was investigated in the unstimulated and lipopolysaccharide‐stimulated primary rat mixed glial cell cultures. In the unstimulated cultures, haloperidol at all applied concentrations, risperidone at 5, 10 &mgr;M and chlorpromazine at 10 &mgr;M increased IL‐10 levels in the culture supernatants without a significant influence on IL‐1&bgr; or TNF‐&agr; levels, and all drugs applied at 10 &mgr;M induced a robust increase in IL‐10 mRNA expression. Under strong inflammatory activation, haloperidol and risperidone at all concentrations reduced production of both pro‐inflammatory cytokines, without adverse effects on IL‐10 expression when used at 10 &mgr;M. Chlorpromazine at all concentrations diminished the production of three cytokines and did not induce anti‐inflammatory effect. These results suggest that dependently on glia activation antipsychotics via different mechanisms may induce anti‐inflammatory effect and that this activity is not common for all drugs under conditions of strong glia activation.

Sex differences in the effect of acute peripheral IL-1β administration on the brain and serum BDNF and VEGF expression in rats.

HighlightsIn females, after IL‐1&bgr; injection serum IL‐1&bgr; levels were higher than in males.In females, IL‐1&bgr; enhanced the pituitary VEGF mRNA and serum VEGF and BDNF levels.In males IL‐1&bgr; reduced BDNF mRNA in the brain structures except for the pituitary.In males, IL‐1&bgr; decreased VEGF mRNA in the amygdala.Sex associated differences concerning BDNF and VEGF were observed in control rats. Abstract The present study was designed to evaluate, for the first time, the potential sex differences in BDNF and VEGF systems under normal conditions and in response to IL‐1&bgr; given ip. Peripheral overproduction of this cytokine mediates the pathophysiology of various acute neuroinflammatory states. Until now, the effect of IL‐1&bgr; on VEGF expression in rat brain structures and its serum level has not been examined. In male and female rats, the BDNF and VEGF mRNA expression, and BDNF level were evaluated in the amygdala, hippocampus, hypothalamus and pituitary gland. The VEGF levels were determined in the pituitary. Serum BDNF and VEGF levels were also measured. The pituitary BDNF mRNA, and BDNF and VEGF levels were higher in females than in male rats whereas in males, the BDNF levels were higher in the other brain structures. The serum BDNF concentration was similar in both groups but VEGF levels were enhanced in females. Following IL‐1&bgr; (50 &mgr;g/kg ip.) administration, a higher serum IL‐1&bgr; level was detected in females than in males. In male rats, IL‐1&bgr; decreased BDNF mRNA in all the brain structures, except for the pituitary, and VEGF mRNA in the amygdala. In opposite, IL‐1&bgr; challenge in females increased the pituitary VEGF mRNA and serum BDNF and VEGF levels. These results suggest that in females BDNF and VEGF may play a more important role in the pituitary function. In males, amygdala trophic system seems to be especially sensitive to the enhanced peripheral IL‐1&bgr; production. Our findings point to the need to consider sex‐related differences to be able to draw reliable conclusions about changes in BDNF and VEGF levels during inflammation.