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==test== 2015

Mechanism wip

Lithium possesses neuroprotective properties by preventing apoptosis and increasing cell longevity.

Oxidative metabolism

Evidence suggests that mitochondrial dysfunction is present in patients with bipolar disorder. Oxidative stress and reduced levels of anti-oxidants(such as glutathione) leads to cell death. Lithium can protect against oxidative stress because it up-regulates complex I and II of the mitochondrial electron transport chain.

Dopamine and G-protein coupling

During mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. Rats treated with lithium were found to have lower dopamine levels causing the brain to inhibit the re-uptake of dopamine. The post-synaptic actions of dopamine are mediated through G-protein coupled receptors. Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmissions. Studies found that in comparison, patients with bipolar disorder had increased G-protein coupling. Lithium treatment alters the function certain subunits of the dopamine associated G-protein, which may contribute to bipolar disorder.

Glutamate and NMDA receptors

Glutamate is a reasonable target for mood stabilization because it is a stimulatory neurotransmitter that has found to be elevated during mania. The NMDA glutamate receptor is structurally complex and is administered in several phychiatric disorders. Normally, Mg will bind to the NMDA receptor and inhibit activation, however when glutamate and glycine bind to the receptor simultaneously, Mg is displaced and the receptor is then activated. This activation increases the available glutamate for post synaptic neurons. The role of Lithium in this process is to further compete with Mg at the NMDA glutamate binding site which stabilizes glutamate neurotransmission as the NMDA receptor is down-regulated which increases glutamate re-uptake which restores glutamate equilibrium. This effect generally reduces glutamate-induced activation and therefore has neuroprotective potential. It has been noted that the NMDA receptor is affected by other neurotransmitters. Lithium administration enhances serotonergic neurotransmission by facilitating the post synaptic serotonin 5-HT1A receptor, which in turn activates the NMDA receptor. This hypothesis is thought to be one of the pathways that Lithium provides long term mood stabilization and anti-manic properties. It has been found that these effects specific to lithium have not been observed in other monovalent ions such as Rb and Cs, and common anti-depressants. Lithium has been shown to reduce dopamine activity, dopamine normally increases NMDA receptor activity via dopamine DI receptors, this is also decreased by the actions of lithium on dopamine.

GABA receptors

GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission. It was found that patients with bipolar disorder had lower GABA levels, which results in excitatory toxicity (increased excitatory neurotransmission) and can cause apoptosis(cell loss). To counter this, lithium reduces the levels of pro-apoptotic proteins by stimulating the release of neuroprotective proteins. Also, lithium is known to increase levels of GABA, which causes a decrease in glutamate levels, down regulating the NMDA receptor.

Cyclic AMP secondary messengers

Cyclic AMP second messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impairs receptor coupled stimulation of cyclic AMP production. It is hypothesized that the dual effects of lithium are due the inhibition of G-proteins that then mediate cyclic AMP production. Receptor mediated production of cyclic AMP is controlled by a stimulatory G-protein, Gs and a counter balancing inhibitory G-protein Gi. Under basal conditions, cyclic AMP production is inhibited by G-protein influence through activation of protein kinase A (PKA). PKA regulates phosphorylation of ion channels cytoskeletal structures, and transcription factors. The cAMP response element binding element (CREB) protein can be activated from the mentioned. It affects the brain-derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (bcl-2) genes which may play a role neuroplasticity. The levels of BDNF are decreased in patients with bipolar disorder. After treatment with lithium, the BDNF and bcl-2 levels are shown to have increased. Increased basal activity of cyclic AMP levels caused by lithium at concentrations of 2mm/L may occur due to lithium reducing activity of Gi by shifting equilibrium between a free active conformation and an inactive heterotrimeric conformation towards the active form. The action of lithium reduces the magnitude of fluctuations in cyclic AMP levels by increasing the lowest basal levels and decreasing maximal stimulated increases, thus stabilizing the activity of the signaling systems. Over a long period of lithium treatment, cAMP and adenylate cyclase levels are further changed by gene transcription factors.

Inositol depletion hypothesis

Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, leading to higher levels of inositol triphosphate. It is known with good certainty that signals from the receptors coupled to the phosphoinositide signal transduction is effected by lithium. Phosphoinositides are important signaling molecules in receptor mediated signal transduction that play a role in central nervous system response. The mechanism starts by activation of a specific Phosphoinositide receptor that results in hydrolysis of phosphoinosital-4-5-biphophate (PIP2) into inositol triphosphate (IP3) and diglyceride through phospholipase C directed activity. PIP2 and diglyceride cause the activation of Protein Kinase C (PKC) and release of intracellular Calcium. IP3 is then phosphorylated by inositol 1-phosphatase (IPPase) and IMPase which results in the recovery of myo-inositol (mI) which is the main reactant in the Phosphoinositide cycle. It is hypothesized that lithium causes the reduction of IMPase and IPPase which lowers cellular levels of mI resulting in the inhibition of the Phosphoinositide cycle.

myo-inositol is also regulated by the high affinity sodium mI transport system (SMIT), resulting in the extracellular mI entering the cell. Lithium is hypothesized to inhibit mI entering the cells and mitigating the function of SMIT.

Animal studies provide uncertain data to support the two part hypothesis. Myo-inisitol levels obtained from sampling the pre-frontal cortex were the same in patients showing signs of mania and patients treated with lithium. It has been reported that lithium treatment has been correlated with decreased mI levels in brains of children which demonstrated reduction in mania symptoms. IMPase and IPPase concentrations are unaffected in normal mood patients when they are exposed to lithium showing that there is lack of evidence for the inositol depletion hypothesis. There is yet sufficient evidence of a direct correlation between lithium and homeostasis of inositiol. Impacts of lithium on phosphoinositide concentrations are different depending on the brain region, cell cycle and endogenous inositol cycles in that region of the brain. This effect was enhanced further with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression.

Protein kinase activity

Protein kinase C (PKC) is found through the brain and effects pre and post-synaptic neurotransmission. PKC is activated by the neurotransmission of the phosopinositide cycle. PKC phosphorylates myristoylated alanine-rich C-kinase substrate(MARCKS), which plays a role in neuron excitability, modulation of gene expression and cell plasticity. Animal studies show that there are increased PKC levels in the pre-frontal cortex of organisms exhibiting mania and bipolar disorder compared to control samples. Within two weeks of lithium treatment at therapeutic concentrations, PKC in platelets of humans with mania had been significantly reduced. Lithium treatment was shown to decrease levels of MARCKS specifically within the hippocampus though the exact mechanism of PKC with regards to bipolar disorder is not known.

GSK3-B

Lithium regulates cytoskeleton protein phosphorylation and function; as a result it affects the neuronal structure. Microtuble-associated proteins(MAPs) such as tau and MAP1B is phosphorylated by lithium, which stabilizes the neuronal cytoskeleton networks.

Protein phosphorylation of cytoskeleton is inhibited by glycogen synthase kinase-3B101. Desphosphorylation of tau at the glycogen synthase kinase-3 site caused by lithium enhances binding of tau to microtubules promoting microtubule assembly. In contrast, dephosphorylation MAP1B decreases ability to bind and stabilize microtubules. Opposing effects of dephosphorylation of tau and MAP-1B promoting microtubule disassembly and assembly respectively causes lithium inhibition of GSK-3.

GSK-3 is an enzyme that is responsible for the regulation of glycogen synthesis. It is directly involved in gene transcription, synaptic plasticity, cell structure and cell resilience. GSK-3 is also implicated to play a role on mood regulation. GSK-3 is shown to be activated in conditions of chronic stress or prolonged exposure to dopamine during periods of mania and is exhibited causation of hyperactivity in mice. Lithium directly inhibits GSK-3 regulation of serine-9 phosphorylation. Inhibition of GSK-3 activates the Akt neurprotective pathway. Inhibition of GSK-3 is not shown to produce anti-depressant effects with great reliability but many studies have shown anti-depressant like effects. In rat models of depression, lithium has shown to increase synaptic plasticity and decrease GSK-3 expression though there are conflicting studies demonstrating that lithium has poor efficacy in the treatment of depressive phase of bipolar disorder.

Intracellular calcium

See Calcium signalling

Maintenance of calcium homeostasis is critical; dys-regulation of intracellular calcium is correlated with bipolar disorder. Subjects with bipolar disorder exhibit elevation of intracellular calcium at both receptor-mediated and basal levels. Calcium levels are a quantitative measurement of the state of the illness rather than a symptom of the bipolar disorder. Lithium has shown effects on intracellular calcium signalling. Lithium blocks the uptake of calcium by cells in individuals with and without bipolar disorder. The reduction in calcium uptake by cells is due to the activation of NMDA receptors. Lithium also activates metabotropic glutamate receptors.

Lithium decreases intracellular calcium stores and levels. Lithium functions by blocking excitotoxic processes, in part by calcium level modulation. Excitotoxic processes are hypothesized to be induced by kainate through the modulation of calcium entry inhibiting calpain proteases involved in apoptosis.

Hypothyroidism done

Most patients treated with lithium carbonate show elevated thyroid stimulating hormone levels in response to injections of thyrotropin-releasing hormone. According to an Australian study, "The incidence of hypothyroidism is six-fold higher in people on lithium as compared to the general population. Hypothyroidism in turn increases the likelihood of developing clinical depression."

Because lithium competes with the receptors for the antidiuretic hormone in the kidney, it increases water output into the urine, a condition called nephrogenic diabetes insipidus. Clearance of lithium by the kidneys is usually successful with certain diuretic medications, including amiloride and triamterene. It increases the appetite and thirst ("polydypsia") and reduces the activity of thyroid hormone (hypothyroidism). The latter can be corrected by treatment with thyroxine and does not require the lithium dose to be adjusted. Lithium is also believed to permanently affect renal function, although this does not appear to be common.

External links

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