Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats

Abstract

There is compelling evidence that withdrawal of neurotrophins can lead to impaired neuronal function and even apoptotic death of neurons. Recent experimental evidence suggests that antidepressant drugs and electroconvulsive treatment might work by enhancing CNS levels of neurotrophins. In addition, Lithium (LI) has been shown to exert robust neuroprotective effects apart from its well known mood-stabilizing effects in humans. In this study we investigated the effects of subchronic (14 days) treatment with various doses of LI on the NGF content of several regions of the adult rat brain. LI treatment, which resulted in prophylactic LI serum concentrations (0.72 ± 0.08 mMol l −1 ), induced a significant (P Ͻ 0.05) increase in NGF concentrations in the frontal cortex (+23.2%), hippocampus (+72%), amygdala (+74%) and limbic forebrain (+46.7%) compared to untreated controls, whereas no effects on NGF concentrations were observed in the striatum, the hypothalamus or the midbrain, even using various LI doses. Moreover, no significant change in NGF concentrations in the frontal cortex was observed after acute (1 day) treatment with LI. Our findings lend support to the notion that an enhancement of NGF production may be specifically involved in the mechanisms of action of antibipolar treatments.

Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol

“…In conclusion, numerous studies have demonstrated lithium's neuroprotective, neurotrophic and antiapoptotic effects [17][18][19][20][21][22][23]35,37 and highlighted the importance of glucocorticoids for hippocampal structure and function. [33][34][35]38,77,78,80 The results reported here add to the concept of bipolar disorder as an illness involving disturbed hippocampal structural plasticity under the opposing influences of lithium and glucocorticoids.…”

“…17,18 Subchronic treatment with lithium also increases nerve growth factor content in hippocampus and induces adult dentate granule cell neogenesis. 19,20 Short-term lithium administration at therapeutic doses to initially depressed bipolar patients elicits distinct brain structural changes including a rise in N-acetyl-aspartate concentration (NAA) and growth of neuropil manifesting as increases in gray matter volume. 21,22 Notably, short-term lithium administration has recently been reported to increase hippocampal volume bilaterally in bipolar patients.…”

Increased Phospholipase A2 Activity and Inflammatory Response But Decreased Nerve Growth Factor Expression in the Olfactory Bulbectomized Rat Model of Depression: Effects of Chronic Ethyl-Eicosapentaenoate Treatment

“…Recently, a neurotrophin hypothesis of depression has been raised because (1) neurodegenerative symptoms occur in depression, which is associated with a decrease in blood or brain concentrations of neurotrophic factors (NTFs), (2) antidepressant treatments increase the expression of NTFs, (3) NTFs can protect noradrenergic and serotonergic neurons, and (4) glucocorticoids and inflammation may suppress NTF synthesis (Mamounas et al, 1995;Quintero et al, 2004;Dranovsky and Hen, 2006;Castrén et al, 2007;Leonard, 2007;Post, 2007;Rajkowska and Miguel-Hidalgo, 2007;Schmidt and Duman, 2007). Decreased nerve growth factor (NGF) has been reported in several animal models of depression (Hellweg et al, 2002;von Richthofen et al, 2003;Schulte-Herbrüggen et al, 2006). However, the relationship between inflammation and NTFs in depression remains unknown.…”

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

“…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] .…”