Melatonin Treatment Enhances Aβ Lymphatic Clearance in a Transgenic Mouse Model of Amyloidosis

Pappolla, Miguel A.; Matsubara, Etsuro; Vidal, Rubén; Pacheco‐Quinto, Javier; Pöeggeler, Burkhard; Zagorski, Michael G.; Sambamurti, Kumar

doi:10.2174/1567205015666180411092551

Cited by 51 publications

(58 citation statements)

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“…> 1 µM, and at these concentrations metabolism is dominant. A recent study on appearance of Aβ in lymph nodes may also reflect the behaviour at higher concentrations as it was performed in mice with mutant APP and high Aβ production rate [ 425 ].…”

Section: Clearance Of Specific Substancesmentioning

confidence: 99%

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Hladky

Barrand

2018

Fluids Barriers CNS

165

156

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This review considers efflux of substances from brain parenchyma quantified as values of clearances (CL, stated in µL g−1 min−1). Total clearance of a substance is the sum of clearance values for all available routes including perivascular pathways and the blood–brain barrier. Perivascular efflux contributes to the clearance of all water-soluble substances. Substances leaving via the perivascular routes may enter cerebrospinal fluid (CSF) or lymph. These routes are also involved in entry to the parenchyma from CSF. However, evidence demonstrating net fluid flow inwards along arteries and then outwards along veins (the glymphatic hypothesis) is still lacking. CLperivascular, that via perivascular routes, has been measured by following the fate of exogenously applied labelled tracer amounts of sucrose, inulin or serum albumin, which are not metabolized or eliminated across the blood–brain barrier. With these substances values of total CL ≅ 1 have been measured. Substances that are eliminated at least partly by other routes, i.e. across the blood–brain barrier, have higher total CL values. Substances crossing the blood–brain barrier may do so by passive, non-specific means with CLblood-brain barrier values ranging from < 0.01 for inulin to > 1000 for water and CO2. CLblood-brain barrier values for many small solutes are predictable from their oil/water partition and molecular weight. Transporters specific for glucose, lactate and many polar substrates facilitate efflux across the blood–brain barrier producing CLblood-brain barrier values > 50. The principal route for movement of Na+ and Cl− ions across the blood–brain barrier is probably paracellular through tight junctions between the brain endothelial cells producing CLblood-brain barrier values ~ 1. There are large fluxes of amino acids into and out of the brain across the blood–brain barrier but only small net fluxes have been observed suggesting substantial reuse of essential amino acids and α-ketoacids within the brain. Amyloid-β efflux, which is measurably faster than efflux of inulin, is primarily across the blood–brain barrier. Amyloid-β also leaves the brain parenchyma via perivascular efflux and this may be important as the route by which amyloid-β reaches arterial walls resulting in cerebral amyloid angiopathy.Electronic supplementary materialThe online version of this article (10.1186/s12987-018-0113-6) contains supplementary material, which is available to authorized users.

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Section: Clearance Of Specific Substancesmentioning

confidence: 99%

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Hladky

Barrand

2018

Fluids Barriers CNS

165

156

View full text Add to dashboard Cite

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“…An important recent observation by Pappolla and co-workers indicate that the administration of melatonin to AD transgenic mice augments the glymphatic clearance of Aβ (132). Relevant to this, melatonin is known to preserve slow wave sleep in patients (148).…”

Section: Resultsmentioning

confidence: 96%

“…As for the experiments of Table 1, theoretical human equivalent doses calculated from Table 3's results ranged from 2-to 3-orders of magnitude greater than those employed in humans. (132) The way in which melatonin exerts its inhibitory effect on the generation of Aβ remains undefined. Melatonin interacts with Aß40 and Aß42 and inhibits progressive β-sheet and/or amyloid fibrils (133,134), an interaction which appears to depend on structural melatonin characteristics rather than on its antioxidant properties (133).…”

Section: Evidence For the Therapeutic Value Of Melatonin In Animal Momentioning

confidence: 99%

Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?

Cardinali

2019

Melatonin Res.

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This review article discusses the special role that melatonin, a molecule with chronobiotic/cytoprotective properties, may have in prevention and treatment of the metabolic syndrome (MS), ischemic and non-ischemic cardiovascular diseases and Alzheimer´s disease (AD). Prevention of these diseases is a major goal for governmental and non-governmental organizations, and melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, merits consideration in this respect. In humans, circulating melatonin levels are consistently reduced in MS, ischemic and non-ischemic cardiovascular diseases and AD, the potential therapeutic value of melatonin being suggested by a limited number of clinical trials generally employing melatonin in the 2-5 mg/day range. In animal model studies of MS, ischemic and non-ischemic cardiovascular diseases and AD melatonin was very effective to curtail symptomatology. However, calculations derived from animal studies indicate projected cytoprotective melatonin doses for humans in the 40-100 mg/day range, doses that are rarely employed clinically. Hence, controlled studies employing melatonin doses in this range are urgently needed. Since the pharmaceutical industry is refractive to support them because of the lack of protective patents for a natural compound, only the involvement of governmental and non-profit organizations can achieve that goal. Within this prospect, the off-label use of melatonin is discussed.

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“…Interestingly, melatonin's pleiotropic effects on the immune system contribute significantly to preventing amyloidogenesis in the brain . Recently, it has been reported that melatonin facilitates Aβ clearance from the brain into the peripheral lymphatic system in a transgenic mouse model (Tg2576), which is clearly evident by an increase in Aβ in the cervical and axillary lymph nodes . Such studies may further lead to investigate the underlying mechanisms of melatonin action on the lymphatic clearance, which would prevent the accumulation of both Aβ and tau.…”

Section: Melatonin Regulates Immune and Inflammatory Signaling In Neumentioning

confidence: 99%

The role of melatonin in targeting cell signaling pathways in neurodegeneration

Shukla

Chinchalongporn

Govitrapong

et al. 2019

Annals of the New York Academy of Sciences

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Melatonin Treatment Enhances Aβ Lymphatic Clearance in a Transgenic Mouse Model of Amyloidosis

Cited by 51 publications

References 0 publications

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?

The role of melatonin in targeting cell signaling pathways in neurodegeneration

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