Effect of Huntington’s and Alzheimer’s Diseases on the Transport of Nicotinic Acid or Nicotinamide Across the Human Blood-Brain Barrier

Hankes, L. V.; Coenen, Heinz H.; Rota, E.; Langen, Karl‐Josef; Herzog, Hans; Wutz, Walter; Stoecklin, Georg; Feinendegen, L. E.

doi:10.1007/978-1-4684-5952-4_91

Cited by 22 publications

(14 citation statements)

References 5 publications

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“…So far it is unclear whether HCA 2 activates Ly-6C Lo monocytes/macrophages before brain infiltration in NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4944 ARTICLE blood or in the ischemic brain. However, the observations that nicotinic acid is able to penetrate into the brain 27 and that nicotinic acid treatment leads to elevated PGD 2 levels in the brain argue for an effect within the CNS. The protective effect of HCA 2 activation depended on COX1 and HPGDS, the key enzymes that synthesize PGD 2 in response to nicotinic acid treatment 17,41 .…”

Section: Discussionmentioning

confidence: 99%

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The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

et al. 2014

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The ketone body b-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA 2 , GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2 À / À mice. We further demonstrate that nicotinic acid, a clinically used HCA 2 agonist, reduces infarct size via a HCA 2 -mediated mechanism, and that noninflammatory Ly-6C Lo monocytes and/or macrophages infiltrating the ischemic brain also express HCA 2 . Using cell ablation and chimeric mice, we demonstrate that HCA 2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA 2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD 2 production by COX1 and the haematopoietic PGD 2 synthase. Our data suggest that HCA 2 activation by dietary or pharmacological means instructs Ly-6C Lo monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

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Section: Discussionmentioning

confidence: 99%

“…7a,d). Nicotinic acid is able to penetrate the blood-brain barrier 27 . Twenty-four hours after MCAO, when monocytes/macrophages have infiltrated the ischemic area, we also found elevated PGD 2 concentrations in the brain on the activation of HCA 2 by nicotinic acid (Fig.…”

Section: Hca 2 Mediates the Neuroprotective Effect Of Ketogenic Dietmentioning

confidence: 99%

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

et al. 2014

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“…Niacin: Positron emission tomography (PET) scans have demonstrated the rapid transfer of both nicotinamide and nicotinate into the brain (Hankes et al, 1991), but the underlying mechanisms are not well understood.…”

Section: Vitaminsmentioning

confidence: 99%

Absorption, Transport, and Retention

Kohlmeier¹

2015

Nutrient Metabolism

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“…Nicotinamide permeates the mammalian BBB based on previous positron emission tomography studies performed in mice [183, 184] and injected radiolabelled precursors [185]. Mice subcutaneously injected with nicotinamide receive profound protection against behavioral defects, demyelination and death from EAE and high increases in NAD [7].…”

Section: Potential Nad-related Pharmacotherapeutic Strategies For mentioning

confidence: 99%

The Importance of NAD in Multiple Sclerosis

Penberthy¹,

Tsunoda²

2009

CPD

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The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and lymphocytes. While IDO activation may keep autoreactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD. Existing data indicate that glia may serve critical functions as an essential supplier of NAD to neurons during times of stress. Administration of pharmacological doses of non-tryptophan NAD precursors ameliorates pathogenesis in animal models of MS. Animal models of MS involve artificially stimulated autoimmune attack of myelin by experimental autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination using Thieler's murine encephalomyelitis virus (TMEV). The Wld S mouse dramatically resists razor axotomy mediated axonal degeneration. This resistance is due to increased efficiency of NAD biosynthesis that delays stress-induced depletion of axonal NAD and ATP. Although the Wld S genotype protects against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated. In this review, we contrast the role of NAD in EAE versus TMEV demyelinating pathogenesis to increase our understanding of the pharmacotherapeutic potential of NAD signal transduction pathways. We speculate on the importance of increased SIRT1 activity in both PARP-1 inhibition and the potentially integral role of neuronal CD200 interactions through glial CD200R with induction of IDO in MS pathogenesis. A comprehensive review of immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis is presented. Distinctive pharmacological approaches designed for NADcomplementation or targeting NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined towards determining which approach may work best in the context of clinical application.

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Effect of Huntington’s and Alzheimer’s Diseases on the Transport of Nicotinic Acid or Nicotinamide Across the Human Blood-Brain Barrier

Cited by 22 publications

References 5 publications

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

Absorption, Transport, and Retention

The Importance of NAD in Multiple Sclerosis

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