Different pharmacokinetics of lithium orotate inform why it is more potent, effective, and less toxic than lithium carbonate in a mouse model of mania.

Lithium carbonate (LiCO) is a mainstay therapeutic for the prevention of mood-episode recurrences in bipolar disorder (BD). Unfortunately, its narrow therapeutic index is associated with complications that may lead to treatment non-compliance. Intriguingly, lithium orotate (LiOr) is suggested to possess unique uptake characteristics that would allow for reduced dosing and mitigation of toxicity concerns. We hypothesized that due to differences in pharmacokinetics, LiOr is more potent with reduced adverse effects. Dose responses were established for LiOr and LiCO in male and female mice using an amphetamine-induced hyperlocomotion (AIH) model; AIH captures manic elements of BD and is sensitive to a dose-dependent lithium blockade. LiCO induced a partial block of AIH at doses of 15 mg/kg in males and 20 mg/kg in females. In contrast, LiOr elicited a near complete blockade at concentrations of just 1.5 mg/kg in both sexes, indicating improved efficacy and potency. Prior application of organic anion transport inhibitors, or inhibition of orotate uptake into the pentose pathway, completely blocked the effects of LiOr on AIH while sparing LiCO effects, confirming differences in transport and compartmentalization between the two compounds. Next, the relative toxicities of LiOr and LiCO were contrasted after 14 consecutive daily administrations. LiCO, but not LiOr, elicited polydipsia in both sexes, elevated serum creatinine levels in males, and increased serum TSH expression in females. LiOr demonstrates superior efficacy, potency, and tolerability to LiCO in both male and female mice because of select transport-mediated uptake and pentose pathway incorporation.

Lithium orotate: A superior option for lithium therapy?

Bipolar disorder (BD) poses a significant public health concern, with roughly one-quarter of sufferers attempting suicide. BD is characterized by manic and depressive mood cycles, the recurrence of which can be effectively curtailed through lithium therapy. Unfortunately, the most frequently employed lithium salt, lithium carbonate (Li2 CO3 ), is associated with a host of adverse health outcomes following chronic use: these unwanted effects range from relatively minor inconveniences (e.g., polydipsia and polyuria) to potentially major complications (e.g., hypothyroidism and/or renal impairment). As these undesirable effects can limit patient compliance, an alternative lithium compound with a lesser toxicity profile would dramatically improve treatment efficacy and outcomes. Lithium orotate (LiC5 H3 N2 O4 ; henceforth referred to as LiOr), a compound largely abandoned since the late 1970s, may represent such an alternative. LiOr is proposed to cross the blood-brain barrier and enter cells more readily than Li2 CO3 , which will theoretically allow for reduced dosage requirements and ameliorated toxicity concerns. This review addresses the controversial history of LiOr, complete with discussions of experimental and clinical efficacy, putative mechanisms of action, adverse effects, and its potential future in therapy.

Astrocytes-The Ultimate Effectors of Long-Range Neuromodulatory Networks?

It was long thought that astrocytes, given their lack of electrical signaling, were not involved in communication with neurons. However, we now know that one astrocyte on average maintains and regulates the extracellular neurotransmitter and potassium levels of more than 140,000 synapses, both excitatory and inhibitory, within their individual domains, and form a syncytium that can propagate calcium waves to affect distant cells via release of "gliotransmitters" such as glutamate, ATP, or adenosine. Neuromodulators can affect signal-to-noise and frequency transmission within cortical circuits by effects on inhibition, allowing for the filtering of relevant vs. irrelevant stimuli. Moreover, synchronized "resting" and desynchronized "activated" brain states are gated by short bursts of high-frequency neuromodulatory activity, highlighting the need for neuromodulation that is robust, rapid, and far-reaching. As many neuromodulators are released in a volume manner where degradation/uptake and the confines of the complex CNS limit diffusion distance, we ask the question-are astrocytes responsible for rapidly extending neuromodulator actions to every synapse? Neuromodulators are known to influence transitions between brain states, leading to control over plasticity, responses to salient stimuli, wakefulness, and sleep. These rapid and wide-spread state transitions demand that neuromodulators can simultaneously influence large and diverse regions in a manner that should be impossible given the limitations of simple diffusion. Intriguingly, astrocytes are ideally situated to amplify/extend neuromodulator effects over large populations of synapses given that each astrocyte can: (1) ensheath a large number of synapses; (2) release gliotransmitters (glutamate/ATP/adenosine) known to affect inhibition; (3) regulate extracellular potassium that can affect excitability and excitation/inhibition balance; and (4) express receptors for all neuromodulators. In this review article, we explore the hypothesis that astrocytes extend and amplify neuromodulatory influences on neuronal networks via alterations in calcium dynamics, the release of gliotransmitters, and potassium homeostasis. Given that neuromodulatory networks are at the core of our sleep-wake cycle and behavioral states, and determine how we interact with our environment, this review article highlights the importance of basic astrocyte function in homeostasis, general cognition, and psychiatric disorders.

Poor Diet, Stress, and Inactivity Converge to Form a "Perfect Storm" That Drives Alzheimer's Disease Pathogenesis.

North American incidence of Alzheimer's disease (AD) is expected to more than double over the coming generation. Although genetic factors surrounding the production and clearance of amyloid-ß and phosphorylated tau proteins are known to be responsible for a subset of early-onset AD cases, they do not explain the pathogenesis of the far more prevalent sporadic late-onset variant of the disease. It is thus likely that lifestyle and environmental factors contribute to neurodegenerative processes implicated in the pathogenesis of AD. Herein, we review evidence that (1) excess sucrose consumption induces AD-associated liver pathologies and brain insulin resistance, (2) chronic stress overdrives activity of locus coeruleus neurons, leading to loss of function (a common event in neurodegeneration), (3) high-sugar diets and stress promote the loss of neuroprotective sex hormones in men and women, and (4) Western dietary trends set the stage for a lithium-deficient state. We propose that these factors may intersect as part of a "perfect storm" to contribute to the widespread prevalence of neurodegeneration and AD. In addition, we put forth the argument that exercise and supplementation with trace lithium can counteract many of the deleterious consequences associated with excessive caloric intake and perpetual stress. We conclude that lifestyle and environmental factors likely contribute to AD pathogenesis and that simple lifestyle and dietary changes can help counteract their effects.

The locus coeruleus neurotoxin, DSP4, and/or a high sugar diet induce behavioral and biochemical alterations in wild-type mice consistent with Alzheimers related pathology.

Alzheimer's disease (AD) is the sixth leading cause of death in the United States where it is estimated that one in three seniors dies with AD or another dementia. Are modern lifestyle habits a contributing factor? Increased carbohydrate (sugar) consumption, stress and disruption of sleep patterns are quickly becoming the norm rather than the exception. Interestingly, seven months on a non-invasive high sucrose diet (20% sucrose in drinking water) has been shown to induce behavioral, metabolic and pathological changes consistent with AD in wild-type mice. As chronic stress and depression are associated with loss of locus coeruleus (LC) noradrenergic neurons and projections (source of anti-inflammatory and trophic factor control), we assessed the ability for a selective LC neurotoxin (DSP4) to accelerate and aggravate a high-sucrose mediated AD-related phenotype in wild-type mice. Male C57/Bl6 mice were divided into four groups: 1) saline injected, 2) DSP4 injected, 3) high sucrose drinking water (20%) or 4) DSP4 injected and high sucrose drinking water. We demonstrate that high sucrose consumption and DSP4 treatment promote an early-stage AD-related phenotype after only 3-4 months, as evidenced by elevated fecal corticosterone, increased despair, spatial memory deficits, increased AChE activity, elevated NO production, decreased pGSK3ß and increased pTau. Combined treatment appears to accelerate and aggravate pathological processes consistent with Alzheimer disease and dementia. Developing a simple model in wild-type mice will highlight environmental and lifestyle factors that need to be addressed to slow, prevent or even reverse the rising trend in dementia patient numbers and cost.