LISPRO mitigates ß-amyloid and associated pathologies in Alzheimer's mice.

Lithium has been marketed in the United States of America since the 1970s as a treatment for bipolar disorder. More recently, studies have shown that lithium can improve cognitive decline associated with Alzheimer's disease (AD). However, the current United States Food and Drug Administration-approved lithium pharmaceutics (carbonate and citrate chemical forms) have a narrow therapeutic window and unstable pharmacokinetics that, without careful monitoring, can cause serious adverse effects. Here, we investigated the safety profile, pharmacokinetics, and therapeutic efficacy of LISPRO (ionic co-crystal of lithium salicylate and l-proline), lithium salicylate, and lithium carbonate (Li2CO3). We found that LISPRO (8-week oral treatment) reduces ß-amyloid plaques and phosphorylation of tau by reducing neuroinflammation and inactivating glycogen synthase kinase 3ß in transgenic Tg2576 mice. Specifically, cytokine profiles from the brain, plasma, and splenocytes suggested that 8-week oral treatment with LISPRO downregulates pro-inflammatory cytokines, upregulates anti-inflammatory cytokines, and suppresses renal cyclooxygenase 2 expression in transgenic Tg2576 mice. Pharmacokinetic studies indicated that LISPRO provides significantly higher brain lithium levels and more steady plasma lithium levels in both B6129SF2/J (2-week oral treatment) and transgenic Tg2576 (8-week oral treatment) mice compared with Li2CO3. Oral administration of LISPRO for 28 weeks significantly reduced ß-amyloid plaques and tau-phosphorylation. In addition, LISPRO significantly elevated pre-synaptic (synaptophysin) and post-synaptic protein (post synaptic density protein 95) expression in brains from transgenic 3XTg-AD mice. Taken together, our data suggest that LISPRO may be a superior form of lithium with improved safety and efficacy as a potential new disease modifying drug for AD.

Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation.

Our previous studies showed that the green tea-derived polyphenolic compound (-)-epigallocatechin-3 gallate (EGCG) reduces amyloid-ß (Aß) production in both neuronal and mouse Alzheimer's disease (AD) models in concert with activation of estrogen receptor-α/phosphatidylinositide 3-kinase/protein kinase B (ERα/PI3K/Akt) signaling and anti-amyloidogenic amyloid precursor protein (APP) α-secretase (a disintegrin and metallopeptidase domain-10, ADAM10) processing. Since the gallate moiety in EGCG may correspond to the 7α position of estrogen, thereby facilitating ER binding, we extensively screened the effect of other gallate containing phenolic compounds on APP anti-amyloidogenic processing. Octyl gallate (OG; 10 µM), drastically decreased Aß generation, in concert with increased APP α-proteolysis, in murine neuron-like cells transfected with human wild-type APP or "Swedish" mutant APP. OG markedly increased production of the neuroprotective amino-terminal APP cleavage product, soluble APP-α (sAPPα). In accord with our previous study, these cleavage events were associated with increased ADAM10 maturation and reduced by blockade of ERα/PI3k/Akt signaling. To validate these findings in vivo, we treated Aß-overproducing Tg2576 mice with OG daily for one week by intracerebroventricular injection and found decreased Aß levels associated with increased sAPPα. These data indicate that OG increases anti-amyloidogenic APP α-secretase processing by activation of ERα/PI3k/Akt signaling and ADAM10, suggesting that this compound may be an effective treatment for AD.

Effects of blue-green algae extracts on the proliferation of human adult stem cells in vitro: a preliminary study.

BACKGROUND: Adult stem cells are known to have a reduced restorative capacity as we age and are more vulnerable to oxidative stress resulting in a reduced ability of the body to heal itself. We have previously reported that a proprietary nutraceutical formulation, NT-020, promotes proliferation of human hematopoietic stem cells in vitro and protects stem cells from oxidative stress when given chronically to mice in vivo. Because previous reports suggest that the blue green algae, Aphanizomenon flos-aquae (AFA) can modulate immune function in animals, we sought to investigate the effects of AFA on human stem cells in cultures. MATERIAL/METHODS: Two AFA products were used for extraction: AFA whole (AFA-W) and AFA cellular concentrate (AFA-C). Water and ethanol extractions were performed to isolate active compounds for cell culture experiments. For cell proliferation analysis, human bone marrow cells or human CD34+ cells were cultured in 96 well plates and treated for 72 hours with various extracts. An MTT assay was used to estimate cell proliferation. RESULTS: We report here that the addition of an ethanol extract of AFA-cellular concentrate further enhances the stem cell proliferative action of NT-020 when incubated with human adult bone marrow cells or human CD34+ hematopoietic progenitors in culture. Algae extracts alone had only moderate activity in these stem cell proliferation assays. CONCLUSIONS: This preliminary study suggests that NT-020 plus the ethanol extract of AFA cellular concentrate may act to promote proliferation of human stem cell populations.

Mecamylamine - a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders.

Mecamylamine (Inversine), the first orally available antihypertensive agent launched in the 1950s, is rarely used today for hypertension because of its widespread ganglionic side effects at antihypertensive doses (25 - 90 mg/day). However, more recent clinical studies suggest that mecamylamine is effective at much lower doses for blocking the central and peripheral effects of nicotine. Pharmacologically, mecamylamine has been well characterized as a nonselective and noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs). Because mecamylamine easily crosses the blood - brain barrier at relatively low doses (2.5 - 10 mg), it has been used by several research groups over the past two decades investigating the role of central nAChRs in the etiology and treatment of various neuropsychiatric disorders, including addiction disorders, Tourette's syndrome, schizophrenia and various cognitive and mood disorders. Two independent Phase II clinical trials recently confirmed mecamylamine's hypothesized antidepressant activity and suggest that it may be effective as an augmentation pharmacotherapy for SSRI treatment resistant major depression. These areas of investigation for mecamylamine are reviewed and recommendations for future research directions are proposed.

EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-gamma: role of JAK/STAT1 signaling and implications for HIV-associated dementia.

Human immunodeficiency virus (HIV)-1 infection of the central nervous system occurs in the vast majority of HIV-infected patients. HIV-associated dementia (HAD) represents the most severe form of HIV-related neuropsychiatric impairment and is associated with neuropathology involving HIV proteins and activation of proinflammatory cytokine circuits. Interferon-gamma (IFN-gamma) activates the JAK/STAT1 pathway, a key regulator of inflammatory and apoptotic signaling, and is elevated in HIV-1-infected brains progressing to HAD. Recent reports suggest green tea-derived (-)-epigallocatechin-3-gallate (EGCG) can attenuate neuronal damage mediated by this pathway in conditions such as brain ischemia. In order to investigate the therapeutic potential of EGCG to mitigate the neuronal damage characteristic of HAD, IFN-gamma was evaluated for its ability to enhance well-known neurotoxic properties of HIV-1 proteins gp120 and Tat in primary neurons and mice. Indeed, IFN-gamma enhanced the neurotoxicity of gp120 and Tat via increased JAK/STAT signaling. Additionally, primary neurons pretreated with a JAK1 inhibitor, or those derived from STAT1-deficient mice, were largely resistant to the IFN-gamma-enhanced neurotoxicity of gp120 and Tat. Moreover, EGCG treatment of primary neurons from normal mice reduced IFN-gamma-enhanced neurotoxicity of gp120 and Tat by inhibiting JAK/STAT1 pathway activation. EGCG was also found to mitigate the neurotoxic properties of HIV-1 proteins in the presence of IFN-gamma in vivo. Taken together, these data suggest EGCG attenuates the neurotoxicity of IFN-gamma augmented neuronal damage from HIV-1 proteins gp120 and Tat both in vitro and in vivo. Thus EGCG may represent a novel natural copound for the prevention and treatment of HAD.