脳由来神経栄養因子

脳由来神経栄養因子（のうゆらいしんけいえいよういんし、BDNF; 英: Brain-derived neurotrophic factor[1]）は、標的細胞表面上にある特異的受容体TrkBに結合し、神経細胞の生存・成長・シナプスの機能亢進などの神経細胞の成長を調節する脳細胞の増加には不可欠な神経系の液性蛋白質である。

BDNFは、ヒトでは、BDNF遺伝子から生成される蛋白質である[2][3][4]。BDNFは、成長因子の中の神経栄養因子の一つであり、標準的な神経成長因子と関連している。神経栄養因子は、脳や末梢で見出される。

BDNFの機能

BDNFは、中枢神経系や末梢神経系の一部のニューロン（神経単位）に作用し、今あるニューロンが維持されるようにサポートし、ニューロンの成長を促し、新しいニューロンやシナプスに分化することを促す[5][6]。脳の中では、BDNFは、海馬、大脳皮質、大脳基底核で活性化されている。それらの部位は、学習、記憶、高度な思考に必須の領域である[7]。BDNFは、網膜、運動ニューロン、腎臓、唾液腺、前立腺にも作用する[8]。

BDNFそれ自体は、長期記憶に重要である[9]。哺乳類の脳にある大多数のニューロンは、胎児期に形成されるのであるが、成人の脳の一部分では、神経幹細胞から、神経発生（neurogenesis）として知られるプロセスにより、新しいニューロンを成長させる能力を維持している。神経栄養因子は、神経発生（ニューロジェネシス）を刺激し、コントロールする化学物質である。BDNFは、最も活性のある神経栄養因子の一つである[10][11][12]。生まれつきBDNFを作ることができないネズミは、脳や感覚神経の発達障害を起こし、通常は出生して間もなく死亡する。このことは、BDNFが正常の神経発達に重要な役割を果たしていることを示唆している[13]。BDNFに構造的に関係している他の重要な神経栄養因子には、NT-3、NT-4、NGFがある。

BDNFノックアウト・マウスの表現型は重篤であり、出生後早期に死亡する。BDNFノックアウト・マウスでは、感覚神経が消失し、協調運動、バランス運動、音の聴取、味覚、呼吸運動を行うことができない。BDNFノックアウトマウスは、小脳に異常があり、交感神経のニューロンの数が増加している[14]。

ある種の身体的運動は、ヒトの脳において、BDNFの合成を3倍程度にまで増加させる。この現象は、運動による神経発生や、運動による認知機能改善の仕組みの一つである[15][16][17][18]。ナイアシン（ビタミンB3）は、BDNFと受容体TrkBを上方制御する[19]。

疾患とBDNF

アルツハイマー病のある人では、脳の組織中のBDNFは低下している。研究によれば、神経栄養因子は、アルツハイマー病のβアミロイド蛋白の毒性に対して、抑制的に働く。

現在、BDNFに関しては自閉症や痛風との関係等、神経疾患治療に応用可能な蛋白質として着目されている。

また、広島大学の栗原英見教授らによってBDNFが歯の関連細胞や血管の増殖、分化を促進することが発見され、歯周再生への関与が見いだされた[20]。すでに動物実験において、BDNFの投与した歯周病モデル動物が健常動物と同様の歯周の状態に回復させることに成功している。一般開業医でも可能な簡単な手術により、歯周病でダメージを受けた歯周を再生できる治療を目指し開発が進行中であり、国際特許を出願をしている。

文献

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  4. ^ Maisonpierre PC, Le Beau MM, Espinosa R, Ip NY, Belluscio L, de la Monte SM, Squinto S, Furth ME, Yancopoulos GD (July 1991). “Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations”. Genomics 10 (3): 558–68. doi:10.1016/0888-7543(91)90436-I. PMID 1889806. 
  5. ^ Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM (March 1995). “A BDNF autocrine loop in adult sensory neurons prevents cell death”. Nature 374 (6521): 450–3. doi:10.1038/374450a0. PMID 7700353. 
  6. ^ Huang EJ, Reichardt LF (2001). “Neurotrophins: Roles in Neuronal Development and Function”. Annu. Rev. Neurosci. 24: 677–736. doi:10.1146/annurev.neuro.24.1.677. PMC 2758233. PMID 11520916. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758233/. 
  7. ^ Yamada K, Nabeshima T (April 2003). “Brain-derived neurotrophic factor/TrkB signaling in memory processes”. J. Pharmacol. Sci. 91 (4): 267–70. doi:10.1254/jphs.91.267. PMID 12719654. 
  8. ^ Mandel AL, Ozdener H, Utermohlen V (July 2009). “Identification of Pro- and Mature Brain-derived Neurotrophic Factor in Human Saliva”. Arch. Oral Biol. 54 (7): 689–95. doi:10.1016/j.archoralbio.2009.04.005. PMC 2716651. PMID 19467646. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716651/. 
  9. ^ Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH (February 2008). “BDNF is essential to promote persistence of long-term memory storage”. Proc. Natl. Acad. Sci. U.S.A. 105 (7): 2711–6. doi:10.1073/pnas.0711863105. PMC 2268201. PMID 18263738. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268201/. 
  10. ^ Zigova T, Pencea V, Wiegand SJ, Luskin MB (July 1998). “Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb”. Mol. Cell. Neurosci. 11 (4): 234–45. doi:10.1006/mcne.1998.0684. PMID 9675054. 
  11. ^ Benraiss A, Chmielnicki E, Lerner K, Roh D, Goldman SA (1 September 2001). “Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain”. J. Neurosci. 21 (17): 6718–31. PMID 11517261. http://www.jneurosci.org/cgi/content/abstract/21/17/6718. 
  12. ^ Pencea V, Bingaman KD, Wiegand SJ, Luskin MB (1 September 2001). “Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus”. J. Neurosci. 21 (17): 6706–17. PMID 11517260. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11517260. 
  13. ^ Ernfors P, Kucera J, Lee KF, Loring J, Jaenisch R (October 1995). “Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice”. Int. J. Dev. Biol. 39 (5): 799–807. PMID 8645564. http://www.intjdevbiol.com/paper.php?doi=8645564. 
  14. ^ MGI database: phenotypes for BDNF homozygous null mice. http://www.informatics.jax.org/searches/allele_report.cgi?_Marker_key=537&int:_Set_key=847156
  15. ^ Szuhany KL, Bugatti M, Otto MW (October 2014). “A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor”. J Psychiatr Res 60C: 56–64. doi:10.1016/j.jpsychires.2014.10.003. PMID 25455510. "Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005). ... Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans" 
  16. ^ Denham J, Marques FZ, O'Brien BJ, Charchar FJ (February 2014). “Exercise: putting action into our epigenome”. Sports Med 44 (2): 189–209. doi:10.1007/s40279-013-0114-1. PMID 24163284. "Aerobic physical exercise produces numerous health benefits in the brain. Regular engagement in physical exercise enhances cognitive functioning, increases brain neurotrophic proteins, such as brain-derived neurotrophic factor (BDNF), and prevents cognitive diseases [76–78]. Recent findings highlight a role for aerobic exercise in modulating chromatin remodelers [21, 79–82]. ... These results were the first to demonstrate that acute and relatively short aerobic exercise modulates epigenetic modifications. The transient epigenetic modifications observed due to chronic running training have also been associated with improved learning and stress-coping strategies, epigenetic changes and increased c-Fos-positive neurons ... Nonetheless, these studies demonstrate the existence of epigenetic changes after acute and chronic exercise and show they are associated with improved cognitive function and elevated markers of neurotrophic factors and neuronal activity (BDNF and c-Fos). ... The aerobic exercise training-induced changes to miRNA profile in the brain seem to be intensity-dependent [164]. These few studies provide a basis for further exploration into potential miRNAs involved in brain and neuronal development and recovery via aerobic exercise." 
  17. ^ Phillips C, Baktir MA, Srivatsan M, Salehi A (2014). “Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling”. Front Cell Neurosci 8: 170. doi:10.3389/fncel.2014.00170. PMC 4064707. PMID 24999318. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064707/. "Moreover, recent evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors. ... Studies have demonstrated the intensity of exercise training is positively correlated with BDNF plasma levels in young, healthy individuals (Ferris et al., 2007). Resistance exercise has also been shown to elevate serum BDNF levels in young individuals (Yarrow et al., 2010). Moreover, it has been shown that moderate levels of physical activity in people with AD significantly increased plasma levels of BDNF (Coelho et al., 2014). ... In humans, it has been shown that 4 h of rowing activity leads to increased levels of plasma BDNF from the internal jugular (an indicator of central release from the brain) and radial artery (an indicator of peripheral release; Rasmussen et al., 2009). Seifert et al. (2010) reported that basal release of BDNF increases following 3 months endurance training in young and healthy individuals, as measured from the jugular vein. These trends are augmented by rodent studies showing that endurance training leads to increased synthesis of BDNF in the hippocampal formation (Neeper et al., 1995, 1996). ... Both BDNF and IGF-1 play a significant role in cognition and motor function in humans. ... Multiple large-scale studies in humans have shown that serum levels of IGF-1 are correlated with fitness and as well as body mass indices (Poehlman and Copeland, 1990). Furthermore, animal studies have shown that exercise in rats is associated with increased amounts of IGF-1 in the CSF." 
  18. ^ Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J (November 2014). “Organ-Specific Physiological Responses to Acute Physical Exercise and Long-Term Training in Humans”. Physiology (Bethesda) 29 (6): 421–436. doi:10.1152/physiol.00067.2013. PMID 25362636. "The Effects of Acute Exercise
    Studies in humans and animals have shown that brain blood flow remains largely unchanged in response to acute exercise[,] ... does not increase with increasing exercise intensity[, and] ... increased metabolic demands of active brain parts are mostly met by redistributing oxygen supply, although changes in oxygen extraction may also contribute. During exercise, blood flow is directed to the areas controlling locomotor, vestibular, cardiorespiratory, and visual functions (8, 91), facilitated by direct communication of neurons and vascular cells (94, 134). ... with increasing exercise intensity, brain glucose uptake decreases (75) as the uptake and utilization of lactate is enhanced (65, 139, 182). Regional differences in brain glucose uptake are also evident, which is furthermore influenced by the level of physical fitness. Thus the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex during exercise is significantly more pronounced in subjects with higher exercise capacity (75) ...
    The Effects of Long-Term Exercise Training
    [A] physically active lifestyle has been shown to lead to higher cognitive performance and delayed or prevented neurological conditions in humans (71, 101, 143, 191). ... The production of brain-derived neurotrophic factor (BDNF), a key protein regulating maintenance and growth of neurons, is known to be stimulated by acute exercise (145), which may contribute to learning and memory. BDNF is released from brain already at rest but increases two- to threefold during exercise, which contributes 70–80% of circulating BDNF (145)."     
  19. ^ Fu L, Doreswamy V, Prakash R (2014). “The biochemical pathways of central nervous system neural degeneration in niacin deficiency”. Neural Regen Res 9 (16): 1509–1513. doi:10.4103/1673-5374.139475. PMC 4192966. PMID 25317166. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192966/. "Recent evidences suggest that niacin administration may up-regulate the expression of BDNF-TrkB. ... At present, we can safely raise the possibility that niacin-mediated neural growth by the BDNF-TrkB pathway could be at least partially mediated by enhanced HDL-C levels." 
  20. ^ Takeda K, Shiba H, Mizuno N, Hasegawa N, Mouri Y, Hirachi A, Yoshino H, Kawaguchi H, Kurihara H (2005). “Brain-derived neurotrophic factor enhances periodontal tissue regeneration”. Tissue Eng. 11: 1618–1629. doi:10.1089/ten.2005.11.1618. PMID 16259615. 

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