Enhancing Synaptogenesis in Diseases Characterized by Deficiencies in Brain Synapses

The loss of hippocampal and cortical synapses, resulting from impaired synaptogenesis, accelerated synaptic degeneration, or both, is one of the earliest neuropathologic findings in Alzheimer’s Disease and is the finding that best correlates with cognitive symptoms (DeKosky and Scheff, 1990; Terry et al., 1991; Selkoe, 2002). A similar decrease in brain synapses is an early finding in an animal model of AD which overproduces A-beta peptides (Jacobsen et al., 2006), and aggregates of such peptides, applied locally to the brain, can also damage synapses, distort neurites, and decrease the numbers of the dendritic spines which are essential precursors for glutamatergic synapses (Jacobsen et al., 2006; Spires-Jones et al., 2007; Knobloch and Mansuy, 2008). These observations have supported the widely-held view that a treatment that would block the synthesis of A-beta or remove it from the circulation, might – by depleting its levels in brain – slow the loss of synapses in AD and thereby sustain cognitive functions in patients. A generation of creative and diligent researchers has provided us with abundant information about A-beta’s synthesis, fates, and toxic effects, and this information has been used to generate rationally-designed drug candidates for treating the disease. However to date none of these candidates – even ones shown to reduce brain levels of A-beta oligomers and senile plaques – has been successful in sustaining cognition

Strategies for enhancing catecholamine-mediated neurotransmission

Major findings made during this project period included the following observations: changes in tyrosine availability do affect brain dopamine release, as assessed by in vivo microdialysis, but that neuronal feedback mechanisms limit the durations of this effect except when dopaminergic neurotransmission has been deficient; the circulating hormone TRH markedly stimulates brain dopamine release, an effect probably mediated by its diketopiperazine metabolite; the amount of circulating L-dopa which enters the brain is both enhanced by carbohydrate consumption and suppressed by protein intake (both nutritional effects can be damaging, inasmuch as a sudden rush of L-dopa into the brain can facilitate dyskinesias, while the inhibition of brain L-dopa uptake by proteins suppresses its conversion to brain dopamine; an appropriate mixture of dietary proteins and carbohydrates can obviate both effects); serotonin release from superfused hypothalamic slices is a linear function of available tryptophan levels throughout the normal dynamic range; the daily rhythm in plasma melatonin levels is abnormal both in the sudden infant death syndrome and in women with secondary amenorrhea; tyrosine can potentiate the anorectic effects of widely-used sympathomimetic drugs; newly-described COMT inhibitors can enhance brain dopamine release in vivo; and a cell culture system, based on Y-79 (retinoblast) cells, exists in which melatonin reliably suppresses dopamine release

Cytidine and Uridine Increase Striatal CDP-Choline Levels Without Decreasing Acetylcholine Synthesis or Release

SUMMARY Aims: Treatments that increase acetylcholine release from brain slices decrease the synthesis of phosphatidylcholine by, and its levels in, the slices. We examined whether adding cytidine or uridine to the slice medium, which increases the utilization of choline to form phospholipids, also decreases acetylcholine levels and release. Methods: We incubated rat brain slices with or without cytidine or uridine (both 25-400 µM), and with or without choline (20-40 µM), and measured the spontaneous and potassium-evoked release of acetylcholine. Results: Striatal slices stimulated for 2 h released 2650 ± 365 pmol of acetylcholine per mg protein when incubated without choline, or 4600 ± 450 pmol/mg protein acetylcholine when incubated with choline (20 µM). Adding cytidine or uridine (both 25-400 µM) to the media failed to affect acetylcholine release whether or not choline was also added, even though the pyrimidines (400 µM) did enhance choline`s utilization to form CDP-choline by 89 or 61%, respectively. The pyrimidines also had no effect on acetylcholine release from hippocampal and cortical slices. Cytidine or uridine also failed to affect acetylcholine levels in striatal slices, nor choline transport into striatal synaptosomes. Conclusion: These data show that cytidine and uridine can stimulate brain phosphatide synthesis without diminishing acetylcholine synthesis or release

Phospholipids and sports performance

Phospholipids are essential components of all biological membranes. Phosphatidylcholine (PC) and Phosphatidylserine (PS) are Phosphatidyl-phospholipids that are required for normal cellular structure and function. The participation in physical activity often challenges a variety of physiological systems; consequently, the ability to maintain normal cellular function during activity can determine sporting performance. The participation in prolonged intense exercise has been shown to reduce circulatory choline concentrations in some individuals. As choline is a pre-cursor to the neurotransmitter Acetylcholine, this finding has encouraged researchers to investigate the hypothesis that supplementation with PC (or choline salts) could enhance sporting performance. Although the available data that evaluates the effects of PC supplementation on performance are equivocal, acute oral supplementation with PC (~0.2 g PC per kg body mass) has been demonstrated to improve performance in a variety of sporting activities where exercise has depleted circulatory choline concentrations. Short term oral supplementation with soy-derived PS (S-PS) has been reported to attenuate circulating cortisol concentrations, improve perceived well-being, and reduce perceived muscle soreness after exercise. More recently, short term oral supplementation (750 mg per day of S-PS for 10 days) has been demonstrated to improve exercise capacity during high intensity cycling and tended to increase performance during intermittent running. Although more research is warranted to determine minimum dietary Phospholipid requirements for optimal sporting performance, these findings suggest that some participants might benefit from dietary interventions that increase the intakes of PC and PS

Melatonin expression in periodontal disease

It was the purpose of this study to examine the relationship between periodontal diseases and melatonin level. Material and Methods:  Forty-six patients with periodontal disease, together with 26 age- and gender-matched healthy controls, were included. Periodontal status was assessed using the Community Periodontal Index. Plasma and salivary melatonin levels were determined using specific commercial radioimmunoassays, whereas lymphocyte subpopulations (e.g. CD3, CD4, CD8, C19 and natural killer cells) were analyzed using flow cytometry. Results:  Patients with periodontal disease had significantly ( p <  0.001) lower plasma (9.46 ± 3.18 pg/mL) and saliva (2.55 ± 0.99 pg/mL) melatonin levels than healthy control patients (14.33 ± 4.05 and 4.22 ± 0.87 pg/mL, respectively). A biphasic relationhip was observed between plasma melatonin levels and Community Periodontal Indices. The plasma melatonin level was reduced in patients with a lower Community Periodontal Index value (1 or 2) and increased in patients with a higher Community Periodontal Index value (3 or 4). Salivary melatonin parallels the changes of plasma melatonin. The higher the Community Periodontal Index, the older the patient and the higher the total lymphocyte counts. CD4 concentrations also increased as the disease worsened. Conclusion:  The results obtained from this study suggest that melatonin could act as a protective function in fighting periodontal infection. However, further studies in this area are encouraged.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65967/1/j.1600-0765.2007.00978.x.pd