NGF and BDNF: from nerves to adipose tissue,
from neurokines to metabokines

NGF e BDNF: dal tessuto nervoso a quello adiposo,
dalle neurochine alle metabochine

GEORGE N. CHALDAKOV, ANTON B. TONCHEV, LUIGI ALOE

1Division of Cell Biology, Medical University, Varna, Bulgaria
2Institute of Neurobiology and Molecular Medicine, National Research Council-European Brain Research Institute, Rome, Italy


SUMMARY. Neurotrophins, particularly, NGF and BDNF are now well recognized to mediate a dizzying number of trophobiological effects, ranging from the Rita Levi-Montalcini’s neurotrophic through immunotrophic to metabotrophic effects. These are implicated in the pathogenesis of various diseases including neuropsychiatric and cardiometabolic diseases, such as dementia, depression, type 2 diabetes and obesity that may express a common phenotype and coexistence. Recently, adipobiology (adiposcience) as become a focus of numerous studies showing that the adipose tissue is the body’s largest endocrine organ producing multiple signaling proteins, including NGF and BDNF, all these dubbed adipokines. On the basis of our and other authors’ evidence that low NGF and/or BDNF levels are found in cardiometabolic diseases (atherosclerosis, obesity, type 2 diabetes, metabolic syndrome), a hypothesis of a critical role of neuro-metabotrophic deficit in the pathogenesis of these diseases has been raised. Since NGF and BDNF also exerts various synaptotrophic effects involved in cognitive enhancement, this hypothesis might also be related to neuropsychiatric diseases such as dementia, depression, schizophrenia, autism, Rett syndrome, anorexia nervosa, and bulimia nervosa. Finally, NGF- and BDNF-based therapeutic approach, including ampakines, antidepressants, selective deacetylase inhibitors, statins, peroxisome proliferator-activated receptor gamma agonists, and “brain food” and calorie restriction, is outlined.

KEY WORDS: adipokines, neurotrophins, synaptotrophic effects, metabotrophic effects, ampakines, deacetylase, calorie restriction.


RIASSUNTO. Le neurotrofine, in modo particolare NGF e BDNF, sono ben riconosciute per mediare un numero da capogiro di effetti trofobiologici, partendo da quelli neurotrofici scoperti da Rita Levi-Montalcini attraverso quelli immunotrofici e metabotrofici. Tutte queste funzioni sono coinvolte nella patogenesi di diverse malattie, incluse quelle neuropsichiatriche e cardiometaboliche, quali la demenza, la depressione, il diabete di secondo tipo e l’obesità, malattie che potrebbero esprimere un fenotipo comune e una comorbilità. Recentemente, l’adipobiologia (adiposcienza) è diventata il focus di numerosi studi che hanno dimostrato che il tessuto adiposo è l’organo endocrino più grande del corpo, che produce proteine di segnale multiplo, incluse il NGF e il BDNF, con un significato anche di adipochine. Sulla base dell’evidenza nostra e di altri autori che hanno evidenziato livelli bassi di NGF e/o di BDNF nelle malattie cardiometaboliche (arteriosclerosi, obesità, diabete di secondo tipo, sindrome metabolica), è stata formulata un’ipotesi sul ruolo critico del deficit neurometabotropico nella patogenie di queste malattie. Da quando si è visto che il NGF e il BDNF esercitano anche effetti sinaptotrofici con miglioramento cognitivo, si è ipotizzato che queste neurotrofine potrebbero essere implicate nella patogenesi di malattie neuropsichiatriche come ad esempio la demenza, la depressione, la schizofrenia, l’autismo, la sindrome di Rett, l’anoressia nervosa e la bulimia nervosa. Infine, è appena agli inizi l’approccio terapeutico basato sul NGF e sul BDNF, mediante l’utilizzo di farmaci quali le ampacine, gli antidepressivi, gli inibitori selettivi della deacetilasi, le statine, gli agonisti dei recettori gamma attivanti la proliferazione del peroxisoma, e anche il “brain food” e la restrizione delle calorie.

PAROLE CHIAVE: adipochine, neurotrofine, effetti sinaptotrofici, effetti metabotropici, ampachine, deacetilasi, restrizione calorica.


INTRODUCTION
Growing body of evidence indicates that not only at neuronal (1-6), but also at cardiometabolic level life requires both NGF and BDNF (7-22).
The present review clusters neurotrophic and metabotrophic potentials of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) relevant to the pathogenesis and therapy of neuropsychiatric and cardiometabolic diseases. In other words, NGF and BDNF are herein appreciated as  pleiotrophic signaling molecules, both neurokines (2) and metabokines (metabotrophic factors) (10,23). Note that (i) Angeletti and Levi-Montalcini (24) pointed out to NGF’s “metabolic effects”, (ii) NGF share structural homology with proinsulin (25), and (iii) the term “metabokine” was, as referring to adenosine, introduced by Lukashev, et al. (26).

NEUROTROPHINS
In retrospect, at the end of the 19th century it was envisaged by Santiago Ramon y Cajal but has not been proved that the nerves require trophic support. By a rare combination of scientific reasoning and intuition, the proof was obtained by Rita Levi-Montalcini, Viktor Hamburger and Stanley Cohen in the early 1950’s in Saint Louis, MO, USA, where the first cell growth factor, namely NGF, was discovered (1-4). This was embodied in a conceptual framework now well known as neurotrophic theory, which reveals a pivotal role of effector (target) cells in the control of neuronal differentiation, survival and function via production of NGF and other neurotrophic factors.
The neurotrophin family of proteins consisted of NGF, BDNF, neurotrophin-3 (NT-3), NT-4/5, NT-6, and NT-7 (6). Neurotrophins mediate their effects via ligation of panneurotrophin receptor, p75NTR, and of receptor tyrosine kinase (tropomyosin-related kinase) (Trk), namely, TrkA (for NGF), Trk B (for BDNF and NT-4), and TrkC (for NT-3) (27). Noteworthy, transactivation of Trk receptors by G protein-coupled receptor (27,28) and by adenosine receptors (29) has recently emerged as a novel biology of neurotrophin actions.
As often occurs, the framework of an initial concept of the physiological role of a newly discovered molecules extends in the light of emerging findings. This was also the case with NGF. For about 30 years after its discovery, there have been few reasons given to indicate that NGF acts on noneuronal cells. Thus, it was remarkable to discover that treatment of newborn rats with NGF caused a systemic increase in the number of mast cells (30). Today there is compelling evidence that NGF, in addition to its neurotrophic function, enhances survival and activity of a large number of nonneuronal cells (5,6,31), including immune cells (32), pancreatic beta cells (15), vascular smooth muscle cells (33), cardiomyocytes (22), endothelial cells (34,35), epithelia cells (36), and adipocytes (37-39).
The secretory proforms of NGF and BDNF, pro-NGF and pro-BDNF (40), respectively, are cleaved extracellularly through the tissue type plasminogen activator (tPA)-serine protease plasmin pathway; note that today’s widely administrated cholesterol-lowering drugs, collectively named statins, can induce tPA, hence releasing a mature form of BDNF (41). As discussed below, these cardiometabolic drugs may also be therapeutic for Alzheimer’s disease and possibly other types of dementia. While NGF is upregulated (18,42), BDNF is downregulated by stress and upregulated by learning, antidepressants, histone deacetylase inhibitors, physical activity, and dietary calorie restriction (see below). And disruption of NGF and/or BDNF signaling is a characteristic feature of many central and peripheral nervous system disorders, such as dementia, depression, amyotrophic lateral sclerosis, multiple sclerosis, stroke, neuropathy and eating and nociceptive disorders ( Table 1).

Table 1. Selected list of NGF- and BDNF-related diseases

Neuropsychiatric diseases

Alzheimer’s disease

Mild cognitive impairment

Huntington’s disease

Parkinson’s disease

Human immunodeficiency virus-associated dementia

Amyothrophic lateral sclerosis

Epilepsy

Primary headache

Migraine

Cluster headache

Diabetic neuropathy

Diabetic retinopathy

Diabetic erectile dysfunction

 

Depression

Schizophrenia

Pervasive developmental disorders

Autism

Asperger syndrome

Rett syndrome

Eating disorders

Anorexia nervosa

Bulimia nervosa

Williams syndrome

Down syndrome

 

Cardiometabolic diseases

Atherosclerosis

Obesity*

Metabolic syndrome

Type 2 diabetes mellitus

Kawasaki disease

 

*Recently, the American Psychiatric Association recognizes obesity not just as a metabolic disorder but also as mental, “food addiction” disorder.


Elucidating the molecular mechanisms that maintain and modify (i) neural including synaptic structure and function, and (ii) vascular and metabolic homeodynamics is required for understanding nervous, cognitive and cardiometabolic systems in health and disease. Indeed, NGF and BDNF initially discovered as neural growth factors are also affecting (i) immune cells (32), (ii) blood vessels/angiogenesis (34,35,43,44), (iii) synaptic plasticity and consolidation (45,46) involved in learning and memory (47), (iv) wound healing and tissue repair (9,13,43,48,49), and (v) glucose, lipid, antioxidant and energy metabolism (50,51). Whereas insulin (52,53), vascular endothelial growth factor (34,35,44,54), cytokines (55,56) and the adipokine leptin (57) initially discovered as hypoglycemic, angiogenic, immunotrophic, and anorexigenic factors, respectively, also exert neurotrophic effects, and thus may contribute to cognitive processes (for antidepressant effect of leptin, see 58). Further, cardiometabolic biomarkers such as cholesterol (59,60) and insulin (61) and the incretin glucagon-like peptide-1 (62), respectively atherosclerosis, type 2 diabetes and obesity biomarkers, are recently found to associate with the development of Alzheimer’s disease (53,58,63-71), also suggesting that Alzheimer’s disease might be viewed as type 3 diabetes mellitus (72). Noteworthy, it has been estimated that 40-60% of individuals with schizophrenia and 55-68% of individuals with depression in the United States are overweight or obese due to combination of disease-related factors and/or use of antipsychotic drugs (reviewed by Kolotkin, et al.) (73).
Here we conceptualize available data of NGF and BDNF as related both to cardiometabolic (see below) and neuropsychiatric diseases (74-93; for a re-evaluation of BDNF hypothesis of depression, see 94).

Synaptotrophic neurotrophins
Changes in the stability and density of dendritic spines and the efficacy of synaptic transmission, known as synaptic plasticity, are believed to be general mechanisms underlying many brain functions, specifically learning and memory (45-47).
Today, there is compelling evidence indicating that in addition to their actions on neuronal differentiation and survival, BDNF and TrkB signaling are uniquely important for the process of activity-dependent synaptic plasticity including long-term potentiation and long-term depression (95), dendritic spine density and cytoskeletal dynamics (96,97), synaptic vesicle neurotransmitter release and retrieval (98) underlying various cognitive functions such as learning and memory encoding and storage (87,99,100); synaptotrophic activity of neurotrophins was conceptualized more than 10 years ago (101).
In brief, BDNF is an activity-dependent modulator of neuronal structure and function in the adult brain. Localization of BDNF and its TrkB receptor to glutamate synapses makes this system intriguing as a dynamic, activity-dependent regulator of excitatory transmission that is implicated in the mechanisms of memory storage and mood control (46,102).

Metabotrophic neurotrophins
Recently, NGF and BDNF are increasingly implicated in the control of glucose, lipid and antioxidant metabolism – reviewed by Chaldakov, et al. (103) and Töre, et al. (19). They are also considered anorexigenic signals in the central control of food intake (50,51,104-108). Conversely, mice heterozygous for targeted disruption of BDNF show hyperphagia and obesity. The same phenotype was observed in mice with a reduced expression of TrkB receptor (109). Likewise, it was demonstrated that BDNF is an important downstream effector of melanocortin signaling in the hypothalamus, thus can, synergistically with leptin, modulate food intake (110).
Conceptually, NGF and BDNF as well as other neurotrophic factors were for the first time viewed as metabotrophic factors (10), recently also designated metabokines (23). Hence, over the last 10 years it has been recognized that altered expression of NGF and/or BDNF and their TrkA receptors has also been implicated in the pathogenesis of cardiometabolic diseases (111-117) (Table 1), which were not appreciated in otherwise excellent review on neurotrophins published recently (118).

ADIPOSE TISSUE AND NEUROTROPHIC FACTORS
Although the discovery of first adipose-derived endocrine factor, the serine protease adipsin, is traced back to 1986, it was the discovery of leptin in 1994 (119) that focused many studies on the endocrine function of adipose tissue, thus defining a new field of study, adipobiology (10,120-123). These studies’ results have indeed shifted the paradigm of adipose tissue from a simple energy storage to a major body’s endocrine organ.
In mammals including humans, there are two major subtypes of adipose tissue: white and brown adipose tissue, WAT and BAT, respectively. WAT has a couple of subdivisions, each with unique anatomic, metabolic and secretory properties: intraabdominal or visceral and subcutaneous adipose tissue. In addition to the subcutaneous and visceral compartments, there are many small visceral depots associated with heart, blood vessels, major lymph nodes, ovaries, mammary glands, eyes, bone marrow, also brain and spinal cord (10,122,123).

Secretion by adipose tissue
The adipose-secreted products include an increasing number of signaling proteins, collectively termed adipokines. Adipokines are involved in the regulation of a wide range of biological processes including inflammation, immunity, angiogenesis, neuronal growth and survival, and lipid, glucose and energy metabolism. Recent transcriptomic and proteomic analyses revealed that more than hundred adipokines are secreted by adipose tissue including leptin, adiponectin, resistin, tumor necrosis factor-alpha, interleukins, chemokines, renin, angiotensin, visfatin, retinol-binding protein, plasminogen activator inhibitor-1, tissue factor, C-reactive protein, haptoglobin, pigment epithelium-derived factor, hepatocyte growth factor, transforming growth factor-beta, vascular endothelial growth factor, and agouti protein – reviewed by Chaldakov, et al. (10), Trayhurn, et al. (120) and Töre, et al. (19). Likewise, adipose tissue cells secrete NGF, BDNF, ciliary neurotrophic factor and other factors with neurotrophic action (Table 2), and also various neuropeptides and pituitary-hypothalamic hormones (12,124,125). The adipokines provide communication between adipose tissue and the rest of the body including the brain. Moreover, brain also produces various adipokines such as leptin, adiponectin, and resistin (126,127), whereas leptin exerts neuroprotective action (57) as well as antidepressant-like effect (58).

Table 2. Adipose tissue-produced neurotrophic factors (11,19,104 and references therein)

Nerve growth factor

Brain-derived neurotrophic factor

Ciliary neurotrophic factor

Metallothioneins

Glial cell line-derived neurotrophic factor

Angiopoietin-1

Vascular endothelial growth factor



THERAPY INSIGHT
NGF- and BDNF-based therapeutic pipeline for neuropsychiatric diseases discussed herein (except migraine, cluster headache, and probably epilepsy) may include (i) applying NGF itself (9,13,43,49,128), (ii) targeting the secretory and signaling pathways using existing or novel drugs (129-134), (iii) TrkB transactivation (27-29), (iv) ampakines, small molecules that stimulate Alpha-amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid (AMPA)-type glutamate receptors (102,135,136), (v) selective deacetylase inhibitors (75,137-140), and (vi) “brain food” (21), that is, neuroprotective nutrients including calorie restriction (141-146), also physical activity (147). Whereas a high-fat diet reduces brain BDNF levels and declines cognitive capacity (148). Accordingly, the above mentioned classes of drugs, including calorie restriction mimetics – see, for example, O’Brian and Chu (149) and Nikolova (150) for resveratrol –, require a novel research evaluation as possible pharmaceuticals and nutraceuticals also for cardiometabolic diseases. Meanwhile, NGF and BDNF could be reasonable targets for resveratrol’s therapeutic effects in both neuropsychiatric and cardiometabolic diseases. Further, recent findings have discovered that free fatty acids may influence brain development through binding to G protein-coupled receptor-40 expressed in the hippocampus (151). Interestingly, some widely used drugs for cardiometabolic diseases such as the cholesterol-lowering statins (59,152-155) and peroxisome proliferator-activated receptor gamma agonists (156,157) as well as two novel common players, acetylcholine (158,159) and glucagon like peptide-1 (62,160), have been introduced into diabetes-obesity-dementia link (53,63,66-69,72,81,161). Another crossroad of nerves and adipose tissue may be adipose-derived mesenchymal stem cells, which can differentiate into neurons in BDNF-enriched cultures (162), and thus representing useful tool to treat neuropsychiatric disorders. Note that proNGF can be cleaved proteolytically at dibasic residues and liberates two other peptides beside NGF, LIP1, a 29 amino acid (aa) peptide, and LIP2, a 38 aa peptide (163,164); their synthetic forms may be targets for new drugs in NGF-related diseases.
The challenge for the future is to understand to what extent the effects of NGF and BDNF are interrelated with regards to their neuro-, synapto-, vasculo- and metabotrophic potentials. Further studies should provide answers to the questions of when and how NGF-BDNF/TrkA,B dysfunction appears and leads to both neuropsychiatric and cardiometabolic diseases. It is hope that by bringing the datasets together in these seemingly diverse disorders we can help develop a conceptual novel basis for future studies in the field.


REFERENCES
1. Levi-Montalcini R: The nerve growth factors 35 years later. Science, 1987, 237, 1154-1162.
2. Levi-Montalcini R, Skaper SD, Dal Toso R, Petrelli L, Leon A: Nerve growth factor: from neurotrophin to neurokine. Trends of Neuroscience, 1996, 19, 514-520.
3. Levi-Montalcini R: The saga of the nerve growth factor. Neuroreport, 1998, 9, R71-83.
4. Levi-Montalcini R: From Turin to Stockholm via St. Louis and Rio de Janeiro. Science, 2000, 287, 809.
5. Aloe L, Chaldakov GN (eds): Nerve growth factor in health and disease. Biomedical Reviews, 1999, 10.
6. Aloe L, Calzá L (eds): NGF and related molecules in health and disease. Progress in Brain Research, 2004, 146.
7. Scarisbrick IA, Jones EG, Isackson PJ: Coexpression of mRNAs for NGF, BDNF, and NT-3 in the cardiovascular system of the pre- and postnatal rat. Journal of Neuroscience, 1993, 13, 875-893.
8. Abe T, Morgan DA, Gutterman DD: Protective role of nerve growth factor against postischemic dysfunction of sympathetic coronary innervation. Circulation, 1997, 95, 13-20.
9. Matsuda H, Koyama H, Sato H, Sawada J, Itakura A, Tanaka A, et al.: Role of nerve growth factor in cutaneous wound healing: accelerating effects in normal and healing-impaired diabetic mice. Journal of Experimental Medicine, 1998, 187, 297-306.
10. Chaldakov GN, Stankulov IS, Hristova M, Ghenev PI: Adipobiology of disease: adipokines and adipokine-targeted pharmacology. Current Pharmaceutical Design, 2003, 9, 1023-1031.
11. Chaldakov GN, Fiore M, Tonchev AB, Dimitrov D, Pancheva R, Rančič G, et al.: Homo obesus: a metabotrophin-deficient species. Pharmacology and nutrition insight. Current Pharmaceutical Design, 2007, 13, 2176-2179.
12. Chaldakov GN, Fiore M, Ghenev PI, Sornelli F, Tonchev AB, Aloe L: Neural-immune-endocrine (NIE) interactions in vascular biology: neurotrophins, immune cells, and tunica adiposa. Journal of EndoCardiology. İn press.
13. Generini S, Tuveri MA, Cerinic M, Mastinu F, Manni L, Aloe L: Topical application of nerve growth factor in human diabetic foot ulcers. A study of three cases. Experimental and Clinical Endocrinology and Diabetes, 2004, 112, 542-544.
14. Muangman P, Muffley LA, Anthony JP, Spenny ML, Underwood RA, Olerud JE, et al.: Nerve growth factor accelerates wound healing in diabetic mice. Wound Repair Regeneration, 2004, 12, 44-52.
15. Larrieta ME, Vital P, Mendoza-Rodríguez A, Cerbón M, Hiriart M: Nerve growth factor increases in pancreatic beta cells after streptozotocin-induced damage in rats. Experimental Biology and Medicine, 2006, 231, 396-402.
16. Kangavari S, Oh YS, Zhou S, Youn HJ, Lee MY, Jung WS, et al.: Radiofrequency catheter ablation and nerve growth factor concentration in humans. Heart Rhythm, 2006, 3, 1150-1155.
17. Corsi MM, Dogliotti G, Pedroni F, Palazzi E, Magni P, Chiappelli M, et al.: Plasma nerve growth factor (NGF) and inflammatory cytokines (IL-6 and MCP-1) in young and adult subjects with Down syndrome: an interesting pathway. NeuroEndocrinology Letters, 2006, 27, 773-778.
18. Manni L, Di Fausto V, Chaldakov GN, Aloe L: Brain leptin and nerve growth factor. Are differently affected by stress in male and female mice: possible neuroendocrine and cardio-metabolic implications. Neuroscience Letters, 2007, 426, 39-44.
19. Töre F, Tonchev AB, Fiore M, Tunçel N, Atanassova P, Aloe L, et al.: From adipose tissue protein secretion to adipopharmacology of disease. Immunology Endocrine & Metabolic Agents in Medical Chemistry, 2007, 7, 149-155.
20. Sposato V, Manni L, Chaldakov GN, Aloe L: Streptozotocin-induced diabetes is associated with changes in NGF levels in pancreas and brain. Archives Italiennes de Biologie, 2007, 145, 87-97.
21. Gómez-Pinilla F: Brain foods: the effects of nutrients on brain function. Nature Reviews Neuroscience, 2008, 9, 568-578.
22. Caporali A, Sala-Newby GB, Meloni M, Graiani G, Pani E, Cristofaro B, et al.: Identification of the prosurvival activity of nerve growth factor on cardiac myocytes. Cell Death and Differentiation, 2008, 15, 299-311.
23. Sornelli F, Fiore M, Chaldakov GN, Aloe L: Brain-dervied neurotrophic factor: a new adipokine. Biomedical Reviews, 2007, 18, 85-88.
24. Angeletti PU, Levi-Montalcini R, Calissano P: The nerve growth factor (NGF): chemical properties and metabolic effects. Advances in Embryology and Related Areas of Molecular Biology, 1968, 31, 51-75.
25. Mukherjee SP, Mukherjee C: Similar activities of nerve growth factor and its homologue proinsulin in intracellular hydrogen peroxide production and metabolism in adipocytes. Transmembrane signalling relative to insulin-mimicking effects. Biochemical Pharmacology, 1982, 31, 3163-3172.
26. Lukashev D, Ohta A, Apasov S, Chen JF, Sitkovsky M: Cutting edge: Physiologic attenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosine receptor in vivo. Journal of Immunology, 2004, 173, 21-24.
27. Chao MV, Rajagopal R, Lee FS: Neurotrophin signalling in health and disease. Clinical Science (London), 2006, 110, 167-173.
28. Jeanneteau P, Chao MV: Promoting neurotrophic effects by GPCR ligands. Novartis Foundation Symposium, 2006, 276, 181-189.
29. Mojsilovic-Petrovic J, Arneja A, Kalb RG: Enprofylline protects motor neurons from in vitro excitotoxic challenge. Neuro-degenerative Diseases, 2005, 2, 160-165.
30. Aloe L, Levi-Montalcini R: Mast cells increase in tissues of neonatal rats injected with the nerve growth factor. Brain Research, 1977, 133, 358-366.
31. Chaldakov GN: The NGF is wider than the neuron. Archives Italian of Biology, 2003, 141, 89-92.
32. Aloe L, Tirassa P, Bracci-Laudiero L: Nerve growth factor in neurological and non neurological diseases: basic findings and emerging pharmacological prospectives. Current Pharmaceutical Design, 2001, 7, 113-123.
33. Bono F, Lamarche I, Herbert JM: NGF exhibits a proapoptotic activity for human vascular smooth muscle that is inhibited by TGF-β1. FEBS Letters, 1997, 416, 243-246.
34. Lazarovici P, Marcinkiewicz C, Lelkes PI: Cross talk between the cardiovascular and nervous systems: neurotrophic effects of vascular endothelial growth factor (VEGF) and angiogenic effects of nerve growth factor (NGF) – implications in drug development. Current Pharmaceutical Design, 2006, 12, 2609-2622.
35. Hansen-Algenstaedt N, Algenstaedt P, Schaefer C, Hamann A, Wolfram L, Cingöz G, et al.: Neural driven angiogenesis by overexpression of nerve growth factor. Histochemistry and Cell Biology, 2006, 125, 637-649.
36. Botchkarev VA, Botchkareva NV, Peters EMJ, Paus R: Epithelial growth control by neurotrophins: leads and lessons form the hair follicle. Progress in Brain Research, 2004, 146, 493-513.
37. Wang B, Jenkins JR, Trayhurn P: Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-α. American Journal of Physiology Endocrinology and Metabolism, 2005, 288, E731-E740.
38. Bulló M, Peeraully MR, Trayhurn P: Stimulation of NGF expression and secretion in 3T3-L1 adipocytes by prostaglandins PGD2, PGJ2, and Delta12-PGJ2. American Journal of Physiology, Endocrinology and Metabolism, 2005, 289, E62-67.
39. Bulló M, Peeraully MR, Trayhurn P, Folch J, Salas-Salvadó J: Circulating nerve growth factor levels in relation to obesity and the metabolic syndrome in women. European Journal of Endocrinology, 2007, 157, 303-310.
40. Fahnestock M, Yu G, Coughlin MD: ProNGF: a neurotrophic or an apoptotic molecules? Progess in Brain Research, 2004, 146, 101-110.
41. Tsai SJ: Statins may enhance the proteolytic cleavage of proBDNF: implications for the treatment of depression. Medical Hypotheses, 2007, 68, 1296-1299.
42. Aloe L, Alleva E, Böhm A, Levi-Montalcini R: Aggressive behaviour induces release of nerve growth factor from mouse salivary gland into blood stream. Proceedings of National Academy of Sciences USA, 1986, 83, 6184-6187.
43. Aloe L: Nerve growth factor, human skin ulcers and vascularization. Our experience. Progress in Brain Research, 2004, 146, 515-522.
44. Raab S, Plate KH: Different networks, common growth factors: shared growth factors and receptors of the vascular and the nervous system. Acta Neuropathologica, 2007, 113, 607-626.
45. Lu B: Acute and long-term synaptic modulation by neurotrophins. Progess in Brain Research, 2004, 146, 137-150.
46. Soulé J, Messaoudi E, Bramham CR: Brain-derived neurotrophic factor and control of synaptic consolidation in the adult brain. Biochemical Society Transections, 2006, 34 (Pt 4), 600-604.
47. Lynch G, Rex CS, Chen LY, Gall CM: The substrate of memory: Defects, treatments, and enhancement. European Journal of Pharmacolology, 2008, 585, 2-13.
48. Micera A, Vigneti E, Pickholtz D, Reich R, Pappo O, Bonini S, et al.: Nerve growth factor displays stimulatory effects on human skin and lung fibroblasts, demonstrating a direct role for this factor in tissue repair. Proceedings of National Academy of Science of USA, 2001, 98, 6162-6167.
49. Aloe L, Tirassa P, Lambiase A: The topical application of nerve growth factor as a pharmacological tool for human corneal and skin ulcers. Pharmacological Research, 2008, 57, 253-258.
50. Lebrun B, Bariohay B, Moyse E, Jean A: Brain-derived neurotrophic factor (BDNF) and food intake regulation: a minireview. Autonomic Neuroscience, 2006, 126-127, 30-38.
51. Fujinami A, Ohta K, Obayashi H, Fukui M, Hasegawa G, Nakamura N, et al.: Serum brain-derived neurotrophic factor in patients with type 2 diabetes mellitus: relationship to glucose metabolism and biomarkers of insulin resistance. Clinical Biochemistry, 2008, 41, 812-817.
52. Watson GS, Craft S: The role of insulin resistance in the pathogenesis of Alzheimer’s disease: implications for treatment. CNS Drugs, 2003, 17, 27-45.
53. Craft S: Insulin resistance and Alzheimer’s disease pathogenesis: potential mechanisms and implications for treatment. Current of Alzheimer Research, 2007, 4, 147-152.
54. Góra-Kupilas K, Jośko J: The neuroprotective function of vascular endothelial growth factor (VEGF). Folia Neuropathologica, 2005, 43, 31-39.
55. Otten U, Gadient RA: Neurotrophina and cytokines – intermediaties between the immune and nervous systems. International Journal of Developmental Neuroscience, 1995, 13, 147-151.
56. Shintani F: Cytokines and neurotrophins in psychiatric disorders. Biomedical Reviews, 1999, 10, 69-73.
57. Tang BL: Leptin as a neuroprotective agent. Biochemical and Biophysic Research Communications, 2008, 368, 181-185.
58. Lu XY: The leptin hypothesis of depression: a potential link between mood disorders and obesity? Current Opinion in Pharmacology, 2007, 7, 648-652.
59. Reid PC, Uramo Y, Kodama T, Hamakubo T: Alzheimer’s disease: cholesterol, membrane rafts, isoprenoids and statins. Journal of Cellular and Molecular Medicine, 2007, 11, 383-392.
60. Xiong H, Callaghan D, Jones A, Walker DG, Lue LF, Beach TG, et al.: Cholesterol retention in Alzheimer’s brain is responsible for high beta- and gamma-secretase activities and Abeta production. Neurobiology of Disease, 2008, 29, 422-437.
61. Nelson TJ, Alkon DL: Insulin and cholesterol pathways in neuronal function, memory and neurodegeneration. Biochemical Society Transactions, 2005, 33, 1033-1036.
62. Perry TA, Greig NH: A new Alzheimer’s disease interventive strategy: GLP-1. Current Drug Targets, 2004, 5, 565-571.
63. Bissels GJ, Staekonborg S, Brunner E, Brayne C, Sheltens P: Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurology, 2006, 5, 64-74.
64. Sima AA, Li ZG: Diabetes and Alzheimer’s disease – is there a connection? Review of Diabetes Study, 2006, 3, 161-168.
65. Simon GE, Von Korff M, Saunders K, Miglioretti DL, Crane PK, van Belle G, et al.: Association between obesity and psychiatric disorders in the US adult population. Archives of General Psychiatry, 2006, 63, 824-830.
66. Li L, Hölscher C: Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Research Reviews, 2007, 56, 384-402.
67. Li ZG, Zhang W, Sima AA: Alzheimer-like changes in rat model of spontaneous diabetes. Diabetes, 2007, 56, 1817-1824.
68. Luchsinger JA, Mayeux R: Adiposity and Alzheimer’s disease. Current Alzheimer Research, 2007, 4, 127-134.
69. Whitmer RA: The epidemiology of adiposity and dementia. Current Alzheimer Research, 2007, 4, 117-122.
70. Beydoun MA, Beydoun HA, Wang Y: Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. Obesity Review, 2008, 9, 204-218.
71. Petry NM, Barry D, Pietrzak RH, Wagner JA: Overweight and obesity are associated with psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Psychosomatic Medicine, 2008, 70, 288-297.
72. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM: Intracerebral streptozotocin model of type 3 diabetes: relevance to sporatic Alzheimer’s disease. Journal of Alzheimer’s Disease, 2006, 9, 13-33.
73. Kolotkin RL, Corey-Lisle PK, Crosby RD, Swanson JM, Tuomari AV, L’Italien GJ, et al.: Impact of obesity on health-related quality of life in schizophrenia and bipolar disorders. Obesity, 2008, 16, 749-754.
74. Calamandrei G, Alleva E, Cirulli F, Queyras A, Volterra V, Capirci O, et al.: Serum NGF levels in children and adolescents with either Williams syndrome or Down syndrome. Developmental Medicine and Child Neurolology, 2000, 42, 746-750.
75. Huang Y, Doherty JJ, Dingledine R: Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus. Journal of Neuroscience, 2002, 22, 8422-8428.
76. Villoslava P, Genain CP: Role of nerve growth factor and other trophic factors in brain inflammation. Progress in Brain Research, 2004, 146, 403-414.
77. Monteleone P, Fabrazzo M, Martiadis V, Serritella C, Pannuto M, Maj M: Circulating brain-derived neurotrophic factor is decreased in women with anorexia and bulimia nervosa but not in women with binge-eating disorder: relationships to co-morbid depression, psychopathology and hormonal variables. Psychological Medicine, 2005, 35, 897-905.
78. Hashimoto K, Koizumi H, Nakazato M, Shimizu E, Iyo M: Role of brain-derived neurotrophic factor in eating disorders: recent findings and its pathophysiological implications. Progress in Neuropsychopharmacology and Biological Psychiatry, 2005, 29, 499-504.
79. Blandini F, Rinaldi L, Tassorelli C, Sances G, Motta M, Samuele A, et al.: Peripheral levels of BDNF and NGF in primary headaches. Cephalalgia, 2006, 26, 136-142.
80. Chang Q, Khare G, Dani V, Nelson S, Jaenisch R: The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron, 2006, 49, 341-348.
81. Manning S: Diabetes and dementia: a common link of coincidental coexistence. Biomedical Reviews, 2007, 18, 59-64.
82. Chen Y, Yang R, Yao L, Sun Z, Wang R, Dai I: Diffrential expression of neurotrophins in penises of streptozotocin-induced diabetic rats. Journal of Andrology, 2007, 28, 306-312.
83. Sarchielli P, Mancini ML, Floridi A, Coppola F, Rossi C, Nardi K, et al.: Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome. Journal of Pain, 2007, 8, 737-745.
84. Mercader JM, Fernández-Aranda F, Gratacòs M, Ribasés M, Badía A, Villarejo C, et al.: Blood levels of brain-derived neurotrophic factor correlate with several psychopathological symptoms in anorexia nervosa patients. Neuropsychobiology, 2007, 56, 185-190.
85. Ahmed F, Tessarollo L, Thiele C, Mocchetti I: Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain. Brain Research, 2008, 1227, 1-11.
86. Azoulay D, Urshansky N, Karni A: Low and dysregulated BDNF secretion from immune cells of MS patients is related to reduced neuroprotection. Journal of Neuroimmunology, 2008, 195, 186-193.
87. Lu B, Martinowich K: Cell biology of BDNF and its relevance to schizophrenia. Novartis Foundation Symposium, 2008, 289, 119-129.
88. Makar TK, Trisler D, Sura KT, Sultana S, Patel N, Bever CT: Brain derived neurotrophic factor treatment reduces inflammation and apoptosis in experimental allergic encephalomyelitis. Journal of Neurological Science, 2008, 270, 70-76.
89. Ognibene E, Adriani W, Caprioli A, Ghirardi O, Ali SF, Aloe L, et al.: The effect of early maternal separation on brain-derived neurotrophic factor and monoamine levels in adult heterozygous reeler mice. Progress in Neuropsychopharmacology and Biological Psychiatry, 2008, 32, 1269-1276.
90. Martinowich K, Lu B: Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology, 2008, 33, 73-83.
91. Post JI, Eibl JK, Ross GM: Zinc induces motor neuron death via a selective inhibition of brain-derived neurotrophic factor activity. Amyotrophic Lateral Sclersis, 2008, 9, 149-155.
92. Karamoysoyli E, Burnand RC, Tomlison DR, Gardiner NJ: Neuritin mediates nerve growth factor-induced axonal regeneration and is deficient in experiemantal diabetic neuropathy. Diabetes, 2008, 57, 181-189.
93. Park KS, Kim SS, Kim JC, Kim HC, Im YS, Ahn CW, et al.: Serum and tear level of nerve growth factor in diabetic retinopathy patients. American Journal of Ophthalmology, 2008, 145, 432-437.
94. Groves JO: Is it time to reassess the BDNF hypothesis of depression? Molecular Psychiatry, 2007, 12, 1079-1088.
95. Zhou, et al.: 2008.
96. Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G: Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. Journal of Neuroscience, 2007, 27, 3017-3029.
97. Chapleau CA, Carlo ME, Larimore JL, Pozzo-Miller L: The actions of BDNF on dendritic spine density and morphology in organotypic slice cultures depend on the presence of serum in culture media. Journal of Neuroscience Methods, 2008, 169, 182-190.
98. Tyler WJ, Perrett SP, Pozzo-Miller LD: The role of neurotrophins in neurotransmitter release. Neuroscientist, 2002, 8, 524-531.
99. Gómez-Palacio Schjetnan A, Escobar-Rodríguez ML: Memory coding and retention: brain-derived neurotrophic factor (BDNF) in synaptic plasticity. Revista de Neurología, 2007, 45, 409-417.
100. Tongiorgi E: Activity-dependent expression of brain-dervied neurotrophic factor in dendrites: Facts and open questions. Neuroscience Research, 2008, 61, 335-346.
101. Snider WD, Lichtman JW: Are neurotrophins synaptotrophins? Molecular and Cellular Neuroscience, 1996, 7, 433-442.
102. Lynch G: Glutamate-based therapeutic approaches: ampakines. Current Opinion in Pharmacology, 2006, 6, 82-88.
103. Chaldakov GN, Fiore M, Hristova MG, Aloe L: Metabotrophic potential of neurotrophins: implication in obesity and related diseases? Medical Science Monitor, 2003, 9, HY19-21.
104. Williams LR: Hypophagia is induced by intracerebroventricular administration of nerve growth factor. Experimental Neurology, 1991, 113, 31-37.
105. Ham, et al.: 2006.
106. Nicholson JR, Peter JC, Lecourt AC, Barde YA, Hofbauer KG: Melanocortin-4 receptor activation stimulates hypothalamic brain-derived neurotrophic factor release to regulate food intake, body temperature and cardiovascular function. Journal of Neuroendocrinology, 2007, 19, 974-982.
107. Yamanaka M, Itakura Y, Tsuchida A, Nakagawa T, Noguchi H, Taiji M: Comparison of the antidiabetic effects of brain-derived neurotrophic factor and thiazolidinediones in obese diabetic mice. Diabetes Obesity and Metabolism, 2007, 9, 879-888.
108. Yamanaka M, Itakura Y, Ono-Kishino M, Tsuchida A, Nakagawa T, Taiji M: Intermittent administration of brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism and prevents pancreatic exhaustion in diabetic mice. Journal of Bioscience and Bioengenering, 2008, 105, 395-402.
109. Xu, et al.: 2003.
110. Bariohay B, Lebrun B, Moyse E, Jean A: Brain-derived neurotrophic factor plays a role as an anorexigenic factor in the dorsal vagal complex. Endocrinology, 2005, 146, 5612-5620.
111. Falcini F, Cerinic MM, Ermini M, Generini S, Lombardi A, Pignone A, et al.: Nerve growth factor circulating levels are increased in Kawasaki disease: correlation with disease actvity and reduced angiotensin converting enzyme levels. Journal of Rheumatology, 1996, 23, 1798-1802.
112. Chaldakov GN, Fiore M, Stankulov IS, Manni L, Hristova MG, Antonelli A, et al.: Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardivascualr disease? Progress in Brain Research, 2004, 146, 279-289.
113. Geroldi D, Minoretti P, Emanuele E: Brain-derived neurotrophic factor and the metabolic syndrome: more than just hypothesis. Medical Hypotheses, 2006, 67, 195-196.
114. Hasan W, Jama A, Donohue T, Wernli G, Onyszchuk G, Al-Hafez B, et al.: Sympathetic hyperinnervation and inflammatory cell NGF synthesis following myocardial infarction in rats. Brain Research, 2006, 1124, 142-154.
115. Manni L, Nikolova V, Vyagova D, Chaldakov GN, Aloe L: Reduced plasma levels of NGF and BDNF in patients with acute coronary syndromes. International Journal of Cardiology, 2005, 102, 169-171.
116. Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P, Rasmussen P, Erikstrup C, et al.: Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia, 2007, 50, 431-438.
117. Pedersen BK: Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia, 2007, 50, 431-438.
118. Schulte-Herbrüggen O, Braun A, Rochlitzer S, Jockers-Scherübl MC, Hellweg R: Neurotrophic factors: a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases? Current Medicinal Chemistry, 2007, 14, 2318-2329.
119. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature, 1994, 372, 425-432.
120. Trayhurn P, Wood IS: Adipokines: inflammation and pleiotropic role of white adipose tissue. British Journal of Nutrition, 2004, 92, 347-355.
121. Catalán V, Rodriguez A, Becerril S, Sainz N, Gómez-Ambrosi J, Frühbeck G: Adipopharmacology of inflammation and insulin resistance. Biomedical Reviews, 2006, 17, 43-51.
122. Guzik TJ, Marvar PJ, Czesnikiewicz-Guzik M, Korbut R: Perivascular adipose tissue as a messenger of the brain-vascular axis: role in vascular inflammation and dysfunction. Journal of Physiology and Pharmacology, 2007, 58, 591-610.
123. Iacobellis G, Sharma AM: Epicardial adipose tissue as new cardio-metabolic risk marker and potential therapeutic target in the metabolic syndrome. Current Pharmaceutical Design, 2007, 13, 2180-2184.
124. Schäffler A, Schölmerich J, Buechler C: Hypothesis paper. Brain talks with fat – evidence for a hypothalamic-pituitary-adipose axis? Neuropeptides, 2005, 39, 363-367.
125. Schäffler A, Schölmerich J, Buechler C: The role of “adipotrophins” and the clinical importance of a potential hypothalamic-pituitary-adipose axis. Nature Clinical Practic Endocrinolology and Metabolism, 2006, 2, 374-383.
126. Wilkinson M, Brown R, Imran SA, Ur E: Adipokine gene expression in brain and pituitary gland. Neuroendocrinology, 2007, 86, 191-209.
127. Brown R, Thompson HJ, Imran SA, Ur E, Wilkinson M: Traumatic brain injury induces adipokine gene expression in rat brain. Neuroscience Letters, 2008, 432, 73-78.
128. Di Fausto V, Fiore M, Tirassa P, Lambiase A, Aloe L: Eye drop NGF administration promotes the recovery of chemically injured cholinergic neurons of adult mouse forebrain. European Journal of Neuroscience, 2007, 26, 2473-2480.
129. Geerts H: AIT-082 (NeoTherapeutics Inc). Drugs, 1998, 1, 694-699.
130. Angelucci F, Mathe AA, Aloe L: Neurotophic factors and CNS disorders: findings in rodent models of depression and schizophrenia. Progress in Brain Research, 2004, 146, 151-165.
131. Rantamäki T, Castrén E: Targeting TrkB neurotrophin receptor to treat depression. Expert Opinions in Therapeutic Targets, 2008, 13, 705-715.
132. Kozisek ME, Middlemas D, Bylund DB: Brain-dervied neurotrophic facts and its receptor tropomyosin-related kinase B in the mechanism of action of antidepressant therapies. Pharmacology and Therapy, 2008, 117, 30-51.
133. Sun MK, Alkon DL: Effects of 4-methylcatechol on spatial memory and depression. Neuroreport, 2008, 19, 355-359.
134. Fiore M, Di Fausto V, Iannitelli A, Aloe L: Clozapine or haloperidol in rats prenatally exposed to methylazoxymethanol, a compound inducing entorhinal-hippocampal deficits, alter brain and blood neurotrophins’ concentrations. Annals of Institute Superior Sanita, 2008, 44, 167-177.
135. Danysz W: CX-516 Cortex pharmaceuticals. Current Opinion in Investigation of Drugs, 2002, 3, 1081-1088.
136. Lynch G, Gall CM: Ampakines and the threefold path to congnitive enhacement. Trends in Neuroscience, 2006, 29, 554-562.
137. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ: Sustained hippocampal chromatin regulation in mouse model of depression and antidepressant action. Nature Neuroscience, 2006, 9, 519-525.
138. Taniura H, Sng JC, Yoneda Y: Histone modifications in status epilepticus induced by kainate. Histolology and Histopathology, 2006, 21, 785-791.
139. Schroeder FA, Lin CL, Crusio WE, Akbarian S: Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biological Psychiatry, 2007, 62, 55-64.
140. Dompierre JP, Godin JD, Charrin BC, Cordeliéres FP, King SJ, Humbert S, et al.: Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. Journal of Neuroscience, 2007, 27, 3571-3583.
141. Mattson MP, Duan W, Guo Z: Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms. Journal of Neurochemistry, 2003, 84, 417-431.
142. Wang J, Ho L, Qin W, Rocher AB, Seror I, Humala N, et al.: Caloric restriction attenuates beta-amyloid neuropathology in mouse model of Alzheimer’s disease. FASEB Journal, 2005, 19, 659-661.
143. Koizumi H, Hashimoto K, Iyo M: Dietary restriction changes behaviours in brain-derived neurotrophic factor heterozygous mice: role of serotonergic system. European Journal of Neuroscience, 2006, 24, 2335-2344.
144. Pasinetti GM, Zhao Z, Qin W, Ho L, Shrishailam Y, Macgrogan D, et al.: Caloric intake and Alzheimer’s disease. Experimental approaches and therapeutic implications. Interdisciplinary Topics in Gerontology, 2007, 35, 159-175.
145. Kanoski SE, Meisel RL, Mullins AJ, Davidson TL: The effects of energy-rich diets on discrimination reversal learning and on BDNF in the hippocampus and prefrontal cortex of the rat. Behavioral Brain Research, 2007, 182, 57-66.
146. Plunet WT, Streijger F, Lam CK, Lee JH, Liu J, Tetzlaff W: Dietary restriction started after spinal cord injury improves functional recovery. Experimental Neurology, 2008, 213, 28-35.
147. Tang SW, Chu E, Hui T, Helmeste D, Law C: Influence of exercise on serum brain-dervied neurotrophic factor concentrations in healthy human subjects. Neuroscience Letters, 2008, 431, 62-65.
148. Molteni R, Barnard RJ, Ying Z, Roberts CK, Gómez-Pinilla F: A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience, 2002, 112, 803-814.
149. O’Brian CA, Chu F: Molecular targets of resveratrol: Implications to health and disease prevention. In: Aggarwal BB, Shishodia S (eds). Resveratrol in Health and Disease. CRC Press, Taylor & Francis Group, Boca Raton, FL, 2006, pp. 133-178.
150. Nikolova V: Resveratrol: a crossroad of enology and biomedicine. Biomedical Reviews, 2007, 18, 89-101.
151. Tonchev AB: Fatty acids as regulators of hippocampal neurogenesis: the case of GPCR40. Biomedical Reviews, 2007, 18, 69-73.
152. Whitefield JF: Can statins put the brakes on Alzheimer’s disease? Expert Opinions in Investigating Drugs, 2006, 15, 1479-1485.
153. Bifulco M, Malfitano AM, Marasco G: Potential therapeutic role of statins in neurological disorders. Expert Review in Neurotherapy, 2008, 8, 827-837. 
154. Arvanitakis Z, Schneider JA, Wilson RS, Bienias JL, Kelly JF, Evans DA, et al.: Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology, 2008, 70 (19 Pt 2), 1795-1802.
155. Wu H, Lu D, Jiang H, Xiong Y, Qu C, Li B, et al.: Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. Journal of Neurotrauma, 2008, 25, 130-1399.
156. Landreth G: Therapeutic use of agonist of the nuclear receptor PPARgamma in Alzheimer’s disease. Current Alzheimer Research, 2007, 4, 159-164.
157. Jiang Q, Heneka M, Landreth GE: The role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in Alzheimer’s disease: therapeutic implications. CNS Drugs, 2008, 22, 1-14.
158. Sridhar GR, Thota H, Allam AR, Babu CS, Prasad AS, Divakar C: Alzheimer’s disease and type 2 diabetes mellitus: the cholinesterase connection? Lipids Health Disease, 2006, 5, 28.
159. Rao AA, Sridhar GR, Das UN: Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer’s disease. Medical Hypotheses, 2007, 69, 1272-1276.
160. Li L: Is glucagons-like peptide-1 an agent treating diabetes, a new hope for Alzheimer’s disease? Neuroscience Bulletin, 2007, 23, 58-65.
161. Shobab LA, Hsiung GY, Fledman HH: Cholesterol in Alzheimer’s disease. Lancet Neurology, 2005, 4, 841-852.
162. Anghileri E, Marconi S, Pignatelli A, Cifelli P, Galié M, Sbarbati A, et al.: Neuronal differentiation potential of human adipose-derived mesencymal stem cells. Stem Cells and Development, 2008, 17, 909-916.
163. Dicou E: Multiple biological activities for two peptides derived from the nerve growth factor precursor. Biochemical and Biophysical Research Communications, 2006, 347, 833-837.
164. Dicou E: High levels of the proNGF peptides LIP1 and LIP2 in the serum and synovial fluid of rheumatoid arthritis patients: evidence for two new cytokines. Journal of Neuroimmunology, 2008, 194, 143-146.