Lithium neuroprotective

In noncancer-related pharmacology, GSK3 is inhibited by lithium at therapeutic concentrations, implying that the long-established effectiveness of lithium in the treatment of psychiatric mood disorders (and more recently as a neuroprotective agent) may be linked to GSK3 inhibition. Antipsychotics such as haloperidol... 

Mechanism of Action Lithium s pharmacologic mechanism of action is not well understood and probably involves multiple effects. Possibilities include altered ion transport, increased intraneuronal catecholamine metabolism, neuroprotection or increased brain-derived neurotrophic factor, inhibition of second messenger systems, and reprogramming of gene expression.29... 

Mechanism of Action The mechanism of action of divalproex is not well understood. It is known to affect ion transport and enhances the activity of y-aminobutyric acid. Like lithium, it also has possible neuroprotective effects through enhancement of brain-derived neurotrophic factor.31... 

In view of bcl-2 s major neuroprotective and neurotrophic roles, a study was undertaken to determine if lithium, administered at therapeutically relevant concentrations, affects neurogenesis in the adult rodent brain. To investigate the effects of chronic lithium on neurogenesis, mice were treated with therapeutic lithium (plasma levels 0.97 0.20 mM), for 4 weeks. After treatment with lithium for 14 days, the mice were administered single doses of BrdU (bromodeoxyuridine, a thymidine analog which is incorporated into the DNA of dividing cells) for 12 consecutive days. Lithium treatment continued throughout the duration of the... 

Manji HK, Chen G. Lithium upregu-lates the cytoprotective protein bcl-2 in vitro and in the CNS in vivo, a role for neurotrophic and neuroprotective effects in manic-depressive illness. J Clin Psychiatry 2000 61 82-96. 

Manji, H.K., Moore, G.J., and Chen, G. (1999) Lithium at 50 have the neuroprotective effects of this unique cation been overlooked Biol Psychiatry 46 929-940. 

Glycogen synthase kinase-3 Constitutively active enzyme that appears to limit neurotrophic and neuroprotective processes lithium inhibits... 

Bauer M, Alda M, Priller J, Young LT International Group for the Study of Lithium Treated Patients (IGSLI). Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurode-generative disorders. Pharmacopsychiatry. 2003 36(suppl 3) S250-S254. 

Manji, H. K., Moore, G. J. and Chen, G. Lithium at 50 have the neuroprotective effects of this unique cation been overlooked Biol. Psychiat. 46 (1999) 929-940. McElroy, S. L. and Keck, P. E. Pharmacological agents for the treatment of acute bipolar mania. Biol. Psychiat. 48 (2000) 539-557. 

Overall, the evidence that lithium has neuroprotective and neurotropic effects through a variety of mechanisms is striking (21), although whether those findings will evolve into therapies of practical clinical value remains to be seen. 

Comments on the generally favorable effects of lithium on immune function have been summarized (46). The antiviral and neuroprotective properties of lithium were mentioned in a review of the immune system and bipolar disorder (47). The potential benefit of lithium in treating AIDS and AIDS-related dementia, owing in part to its cytokine-regulating and neuroprotective effects, has been reviewed (48). Genital Herpes simplex infection has responded to lithium (49). 

Actually, lithium has been associated with many effects that are believed to be neuroprotective (234). Most importantly, it reduces the activity of glycogen synthase kinase-3 (GSK-3), which leads to reduced production of the tau protein (235,236). However, lithium may actually increase the production of amyloid beta (237), although previous reports have suggested that lithium reduces amyloid beta and its consequent toxicity (238,239). 

Dou H, Ellison B, Bradley J, Kasiyanov A, Poluektova LY, Xiong H, Maggirwar S, Dewhurst S, Gelbard HA, Gendelman HE (2005) Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis. J Neurosci 25 8375-8385. 

Pharmacology and Mechanism of Action. Despite numerous investigations into the biologic and clinical properties of lithium, there is no unified theory for its mechanism of action (see Table 68-10). Chronic lithium administration may modulate gene expression and have neuroprotective effects. 

In animal studies and in isolated human neural cells, lithium has been shown to increase the expression of important neuroprotective proteins. 

This evidence suggests that lithium may exert some of its long-term benefits in the treatment of mood disorders via neuroprotective effects and that hthium may have potential therapeutic properties in neurodegenerative disorders. 

During the past three decades, it has been possible to extend the classical antimanic, antidepressive and recurrent-prophylactic action profile of lithium by an antipsychotic (Alexander et al. 1979), antiaggressive (Nilsson 1994), antisuicidal (Mtiller-Oerlinghau-sen et al. 1992), antineurotic (PfafFenrath et al. 1982) and neuroprotective (Ermidou-Pollet and Pollet 2002) component. Though lithium is even the first-choice treatment in the prophylaxis of chronic and episodic courses of cluster headache in patients, who are aged over 45 years (Pfaf-fenrath et al. 1982), all the results with the antineurotic properties of lithium are based on open trials. Clear evidence of the antineurotic effect of lithium has not yet... 

Cerebellar atrophy CerebeUar atrophy has been reported in a patient who had taken lithium for 20 years without any episodes of toxicity [21 ]. The authors thou t that lithium was the responsible stimulus, since investigations were otherwise negative. However, there is no convincing reason for this, and it is an unlikely event, especially in the setting of the accumulating evidence that lithium is usually neuroprotective [22 ]. 

Dementia Lithium has neuroprotective properties in vivo. In human endothelial cell and rat cortical astrocyte cultures, lithium 0.2 mmol/l increased phosphorylation of GSK-3P (inactivation of GSK-3f) and promoted secretion of vascular endothelial growth factor (VEGF) [2( ]. The effect on GSK-3P may be more general, since lithium also reduced GSK-3 concentrations in primary cultures of rat cortical and hippocampal cells [21 ] and in neural precursor cells [22 ]. This effect on GSK-3j3 expression and activity is probably related to the observation that lithium treatment of primary culture cortical cells reduces both tau protein concentrations and tau phosphorylation (tau is phosphorylated by GSK-3 ) [23 ]. Similarly, in PCI2 cells, lithium 1.2 mmol/l reduced morphine-induced apoptosis by down-regulating the BAX, which is pro-... 

At the organ level, lithium has been associated with an increase in cortical grey matter as examined using structural magnetic resonance imaging (MRI) [25 ] and an increase in N-acetyl-aspartate, a derivative of aspartic acid, which is a marker of neuronal health, measured by magnetic resonance spectroscopy [26 j. These neuroprotective characteristics of lithium may reduce the risk of dementia. 

Amyotrophic lateral sclerosis The neuroprotective effects of lithium suggest that it might be useful in other neurodegenera-tive or neurodestructive conditions. Amyotrophic lateral sclerosis (ALS), a disease... 

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