Effects of lithium and valproate on serum and hippocampal neurotrophin-3 levels in an animal model of mania

Walz, Julio Cesar; Frey, Benício N.; Andreazza, Ana Cristina; Ceresér, Keila Maria Mendes; Cacilhas, Alice Aita de; Valvassori, Samira S.; Quevedo, João; Kapczinski, Flávio

doi:10.1016/j.jpsychires.2007.03.005

Cited by 53 publications

(39 citation statements)

References 28 publications

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“…Besides an increase in BDNF mRNA and protein levels, we also found elevated NT-3 mRNA levels in the retrosplenial cortex. In an adult rat model of bipolar mood disorders, increased NT-3 mRNA expression was found after multiple amphetamine injections [Walz et al, 2008], confirming our results. The presence of NT-3 mRNA in the neonatal cortex following systemic treatment with a single dose of MDMA is a new finding of this study.…”

Section: Discussionsupporting

confidence: 90%

Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

Dzietko

Sifringer²,

Klaus³

et al. 2010

Dev Neurosci

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The incidence of methamphetamine abuse is particularly high in adolescents and is a common problem among women of childbearing age, leading to an increasing number of children with prenatal exposure. MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is an amphetamine-like stimulant and is known to induce apoptotic damage to fine serotonergic fibers in the adult rat brain. Little is known about toxic effects of MDMA and potential underlying molecular mechanisms in the developing brain. Here, we investigated whether MDMA exposure during the period of rapid brain growth causes neurodegeneration in the developing rat brain. MDMA significantly enhanced neuronal death in the brains of 6-day-old rat pups at a dose of 60 mg/kg, but no significant toxicity was detected at the ages of 14 and 21 days. Brain regions mainly affected were the cortex, septum, thalamus, hypothalamus and the cornu ammonis 1 region. To explore possible molecular mechanisms involved in this neurodegenerative process, we investigated the impact of MDMA on the expression of the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor. Neonatal exposure of 6-day-old rats to MDMA triggered a considerable increase in cortical BDNF and NT-3 levels. Moreover, P7 CD1/BDNF knockout mice were noticeably more sensitive to MDMA exposure as compared to their wild-type age-matched littermates. These data suggest that a single injection of MDMA causes neurodegeneration in the neonatal rat brain. The upregulation of BDNF and NT-3 expression may indicate an important compensatory mechanism leading to the survival of neuronal cells in the developing brain.

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Section: Discussionsupporting

confidence: 90%

Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

Dzietko

Sifringer²,

Klaus³

et al. 2010

Dev Neurosci

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“…Changes in NGF and glial cell line-derived neurotrophic factor were observed in a rat model of depression [10] , including significant increases of NGF concentrations in the frontal cortex, limbic forebrain, hippocampus, and amygdala of adult rats [28] . Lithium also increased serum and hippocampal NT-3 levels in an animal model of mania [29] , and upregulated vascular endothelial growth factor in brain endothelial cells and astrocytes [30] . Interestingly, vascular endothelial growth factor has been implicated in neuronal survival, neurotrophic effects, regeneration, growth, and differentiation.…”

Section: Lithium Activates Creb and Increases Bdnf Expressionmentioning

confidence: 96%

Novel Insights into Lithium’s Mechanism of Action: Neurotrophic and Neuroprotective Effects

Quiróz

Machado‐Vieira²,

Zarate³

et al. 2010

Neuropsychobiology

195

134

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The monovalent cation lithium partially exerts its effects by activating neurotrophic and neuroprotective cellular cascades. Here, we discuss the effects of lithium on oxidative stress, programmed cell death (apoptosis), inflammation, glial dysfunction, neurotrophic factor functioning, excitotoxicity, and mitochondrial stability. In particular, we review evidence demonstrating the action of lithium on cyclic adenosine monophosphate (cAMP)-mediated signal transduction, cAMP response element binding activation, increased expression of brain-derived neurotrophic factor, the phosphatidylinositide cascade, protein kinase C inhibition, glycogen synthase kinase 3 inhibition, and B-cell lymphoma 2 expression. Notably, we also review data from clinical studies demonstrating neurotrophic effects of lithium. We expect that a better understanding of the clinically relevant pathophysiological targets of lithium will lead to improved treatments for those who suffer from mood as well as neurodegenerative disorders.

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“…Acute treatment for 1 day had no effect on NGF concenHowever, when dephosphorylated by stress, inflammation, and other signals, they enter the nucleus and turn trations in frontal cortices. Walz et al (324) has reported that lithium increased on growth, protective, inflammatory, and differentiation programs. levels of neurotrophin-3 (NT-3) in the serum and hippocampus of rats that had amphetamine-induced mania, LITHIUM AND NEUROTROPHINS whether lithium was given before, during, or after amphetamine.…”

Section: Lithium-induced Granulocytosismentioning

confidence: 99%

Review of Lithium Effects on Brain and Blood

2009

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Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3β (GSK3β). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/β-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.

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Effects of lithium and valproate on serum and hippocampal neurotrophin-3 levels in an animal model of mania

Cited by 53 publications

References 28 publications

Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

Novel Insights into Lithium’s Mechanism of Action: Neurotrophic and Neuroprotective Effects

Review of Lithium Effects on Brain and Blood

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