Neurotrophic Theory Research Articles

Cajal, the neuronal theory and the idea of brain plasticity.

This paper reviews the importance of Cajal's neuronal theory (the Neuron Doctrine) and the origin and importance of the idea of brain plasticity that emerges from this theory. We first comment on the main Cajal's discoveries that gave rise and confirmed his Neuron Doctrine: the improvement of staining techniques, his approach to morphological laws, the concepts of dynamic polarisation, neurogenesis and neurotrophic theory, his first discoveries of the nerve cell as an independent cell, his research on degeneration and regeneration and his fight against reticularism. Second, we review Cajal's ideas on brain plasticity and the years in which they were published, to finally focus on the debate on the origin of the term plasticity and its conceptual meaning, and the originality of Cajal's proposal compared to those of other authors of the time.

Comparison of Different Modes of Exercise on Cognitive Function and Mood among Older Adults in Mexico

Purpose: The aim of the study was to investigate comparison of different modes of exercise on cognitive function and mood among older adults in Mexico
 Methodology: This study adopted a desk methodology. A desk study research design is commonly known as secondary data collection. This is basically collecting data from existing resources preferably because of its low cost advantage as compared to a field research. Our current study looked into already published studies and reports as the data was easily accessed through online journals and libraries.
 Findings: The study on older adults in Mexico found that regular physical exercise, regardless of the mode, improved cognitive function, particularly memory and executive functions. Aerobic exercises like walking and swimming were effective in enhancing mood by reducing depression and anxiety symptoms. Resistance training benefited attention and concentration. Group exercise sessions and personalized programs boosted adherence and motivation, contributing to improved cognitive outcomes and mood among older adults in Mexico.
 Unique Contribution to Theory, Practice and Policy: The cognitive reserve theory, the neurotrophic theory & the socioemotional selectivity theory may be used to anchor future studies comparison of different modes of exercise on cognitive function and mood among older adults in Mexico Develop practical guidelines for creating customized workout playlists based on individual preferences and exercise goals. Collaborate with workplace wellness programs to incorporate music into physical fitness initiatives. Advocate for policies that support the use of music in corporate fitness centers and wellness activities to improve employee engagement and well-being.

Unfolding the Role of BDNF as a Biomarker for Treatment of Depression.

Depression is a well-known disabling mental illness characterized by sadness, loss of interest in activities, and decreased energy. The symptoms of depression are usually recurrent in vulnerable individuals, and persistence of symptoms significantly impairs individuals' quality of life. The exact pathophysiology of depression remains ambiguous, though many hypotheses have been proposed. Brain-derived neurotrophic factor (BDNF) has recently been reported to play a vital role in the pathophysiology of depression. BDNF is an important neurotrophic factor found in the human brain and is involved in neuronal growth and proliferation, synaptic neurotransmission, and neuroplasticity. The neurotrophic theory of depression proposes that depression results from reduced BDNF levels in the brain, which can be treated with antidepressants to alleviate depressive behavior and increase BDNF levels.The aim of this review is to provide broad insight into the role of BDNF in the pathogenesis of depression and in antidepressant therapy.The studies mentioned in this review article greatly support the role of BDNF in the pathogenesis of depression and treatment of this disorder with antidepressants. Since abnormalities in BDNF levels lead to the production of diverse insults that amplify the development or progression of depression, it is important to study and explore BDNF impairment in relation to depression, neuroplasticity, and neurogenesis, and increasing BDNF levels through antidepressant therapy, showing positive response in the management of depression.

Blues in the Brain and Beyond: Molecular Bases of Major Depressive Disorder and Relative Pharmacological and Non-Pharmacological Treatments.

Despite the extensive research conducted in recent decades, the molecular mechanisms underlying major depressive disorder (MDD) and relative evidence-based treatments remain unclear. Various hypotheses have been successively proposed, involving different biological systems. This narrative review aims to critically illustrate the main pathogenic hypotheses of MDD, ranging from the historical ones based on the monoaminergic and neurotrophic theories, through the subsequent neurodevelopmental, glutamatergic, GABAergic, inflammatory/immune and endocrine explanations, until the most recent evidence postulating a role for fatty acids and the gut microbiota. Moreover, the molecular effects of established both pharmacological and non-pharmacological approaches for MDD are also reviewed. Overall, the existing literature indicates that the molecular mechanisms described in the context of these different hypotheses, rather than representing alternative ones to each other, are likely to contribute together, often with reciprocal interactions, to the development of MDD and to the effectiveness of treatments, and points at the need for further research efforts in this field.

РОЛЬ ЛЕЙКОЦИТАРНЫХ ПРОТЕИНАЗ В ПАТОГЕНЕЗЕ ВОСПАЛИТЕЛЬНЫХ ЗАБОЛЕВАНИЙ ПАРОДОНТА

Subject. Despite the constant efforts of practicing physicians and scientists, the prevalence proportion of inflammatory and destructive periodontal diseases in the world is not subsiding. Previously scientists have examined several different theories on the development of pathological conditions in periodontal tissues, ranging problems from the neurotrophic theory of occurrence to the effect of occlusion injury on periodontal tissues. Theories dealing with the influence of specific and non-specific bacterial plaque have also been studied. None of the theories has become reasonable and single valued. It is believed that the mechanism of the development of the disease is complex, autoimmune, damaging primarily collagen, elastic fibers of the capillary endothelium, gingival ligament and bone tissue. Over the past decade, it has been proven that inflammation in periodontal tissues is initiated and proceeds in response to the introduction of pathogenic bacteria. However, it can be said that not all patients develop an inflammatory response to bacterial invasion. The second important factor in the development and progression of the inflammatory-destructive process is the immune response of a particular individual. Scientists have noted the influence of the non-microbial factor and have come to the conclusion that in the surrounding tissues of the inflamed area there are not only enzymes secreted by bacteria, but also leukocyte proteinases, which in turn are mediators of the tissue destruction. Purpose ― to examine the role of leukocyte proteinases in the pathogenesis of inflammatory periodontal diseases. Methodology. The number of indigenous and foreign literature sources dealing with the study of the role of leukocyte proteinases in the development and maintenance of a destructive inflammatory process has been reviewed by us. Conclusion. The role of the aggressive destructive effect of leukocyte proteinases on periodontal tissues has been analyzed. Leukocyte proteinases are mediators of progressive destruction of connective tissue and can be used as markers to assess the severity of the course and predict the development of the inflammatory process in periodontal tissues.

Manganese modifies Neurotrophin-3 (NT3) and its tropomyosin receptor kinase C (TrkC) in the cortex: Implications for manganese-induced neurotoxicity

Manganese (Mn), an essential micronutrient, has the potential to induce apoptosis. The NT3/TrkC ligand/receptor pair known as part of the classic neurotrophic theory plays a critical role in neuronal survival. However, whether the NT3/TrkC-mediated signaling pathways are involved in Mn-induced apoptosis of cortical neurons remains unknown. The present study was designed to investigate the interactions between NT3/TrkC-mediated signaling pathways and Mn-induced apoptosis in cortical neurons. This study showed that subacute Mn exposure significantly increased the levels of pro-apoptotic Bax while decreasing the levels of anti-apoptotic Bcl 2 in the cortex compared with the corresponding control. Markedly reduced NT3 and TrkC levels along with decreased Ras/MAPK and PI3/Akt signaling in the cortex were observed following subacute Mn exposure. We further found increased levels of Bax, cleaved caspase-3, and the total apoptosis rate, and decreased levels of Bcl 2, NT3, TrkC, and Ras/MAPK and PI3/Akt signaling in Mn-treated primary cortical neurons. Pretreatment with hNT3 or Z-VAD-FAM ameliorated Mn-induced apoptosis by increasing the levels of NT3 and TrkC and its Ras/MAPK and PI3/Akt signaling pathways. Taken together, our findings clearly indicate that NT3/TrkC and mediated Ras/MAPK and PI3/Akt signaling pathways play a crucial role in Mn-induced neurotoxicity.

Editorial: The Real Technology Revolution: Technology Justice

Forearms of juvenile axolotls contain about 5000 axons, of which only 25% are myelinated and visible by light microscopy. Virtually all the axons degenerate after transection of the brachial plexus, but repeated operations fail to keep the arm completely denervated. Regrown nerve fibres were detected by electron microscopy after 6 weeks of attempted denervation and related to the quantity usually considered necessary for limb regeneration. Such arms regenerated quite normally, provided their innervation had been depleted for several weeks before amputation. Among other ways of reconciling these observations to the neurotrophic theory of limb regeneration, it is suggested that tissues can adapt to deprivation of their nerve supply.

Genes of neurotrophic factors and responsiveness to antidepressive psychopharmacotherapy in patients with depressive disorders

Major depressive disorder (MDD) is a clinically and biologically heterogeneous disorder with a heavy personal and socio-economic burden [1]. The neurotrophic theory of the development of depression most fully explains the morphological changes that occur in the brain of patients [2,3]. Among the various neurotrophic factors brain-derived neurotrophic factor (BDNF) and prolactin play an important role in pathogenesis of depression [4]. Objective of the study was to investigate the association of genes polymorphisms of BDNF and prolactin with responsiveness to therapy in patients with MDD. Methods The study group included 185 MDD patients (F32,F33,ICD-10) and 134 healthy persons. Severity of depressive symptoms on the baseline and on the 14th and 28th day of therapy was assessed using Hamilton Depression Scale (HDRS-17) and Clinical Global Impression – Severity scale (CGI-S). Antidepressive therapy response on the 14th and 28th day of therapy was evaluated using Clinical Global Impression – Improvement scale (CGI-I). Genotyping was carried out on polymorphic variants of BDNF genes (rs6265, rs7124442, rs11030104) and PRL gene (rs1341239). The SPSS software was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results The study found no deviation of genotype frequencies from HWE (р > 0.05), except for the SNP rs11030104 in the group of patients (χ2 = 37.540; p = 0.001). Important differences in frequency of genotypes and alleles of SNPs rs11030104 of BDNF and rs1341239 of PRL genes between patients and healthy persons at entry have been found. The final multivariate binary logistic regression analysis shows that the A/A genotype of SNP rs11030104 has a more than 6 times higher risk of developing depression than G/G or G/A genotype (p = 0.009). Allele G of SNP rs1341239 gene was more common in patients (63%) compared to control (59%) (p <0.001). We studied the association between the scores on the HDRS-17, CGI-S and CGI-I scales and gene polymorphisms. A statistically significant reduction in scores on all scales during therapy was observed (p <0.01). A decreased scores on the HDRS-17 is associated with G/G genotype of SNP rs6265 (p = 0.049), C/C genotype of SNP rs7124442 (р = 0.009) and A/A genotype of SNP rs11030104 (p = 0.07), patients with these genotypes are characterized by mild depressive disorder on the 14th day of therapy. We showed a relationship between the carriage of the C allele of SNP rs7124442 (p = 0.014) and the G/G genotype of SNP rs6265 (p = 0.078) and a reduced CGI-S score indicating a good response to therapy in this patients. There was a correlation between the presence of the T allele of SNP rs1341239 and the absence of remission according to the CGI-S scale (p = 0.004) and the worst response to antidepressant therapy. Conclusions Our results suggest that SNPs rs11030104 of BDNF gene and rs1341239 of PRL gene are associated with higher risk of developing depression, SNPs rs6265 and rs7124442 of BDNF gene are probably related to the clinical characteristics of the disorder and the response to pharmacotherapy. Disclosure statement: This study was supported by the Russian Foundation Basic Research, grant No. 17-29-02205 “Development of a molecular-genetic panel of depressive disorders based on polymorphisms of the genes of neuronal kinases, neurotrophic proteins and genes of the serotonergic system”

The dependence receptor TrkC regulates the number of sensory neurons during DRG development

The development of the sensory nervous system is the result of fine-tuned waves of neurogenesis and apoptosis which control the appropriate number of precursors and newly generated neurons and orient them toward a specific lineage. Neurotrophins and their tyrosine-kinase receptors (RTK) orchestrate this process. They have long been in the scope of the neurotrophic theory which established that a neuron is committed to die unless a trophic factor generated by its target provides it with a survival signal. The neural death has thus always been described as a "default" program, survival being the major player to control the number of cells. New insights have been brought by the gain of function studies which recently demonstrated that TrkC (NTRK3) is a "dependence receptor" able to actively trigger apoptosis in absence of its ligand NT-3. In order to address the role of TrkC pro-apoptotic activity in the control of sensory neurons number, we generated a TrkC gene-trap mutant mice. We found out that this new murine model recapitulates the sensory phenotype of TrkC constitutive mutants, with reduced DRG size and reduced number of DRG neurons. We engineered these mice strain with a lacZ reporter in order to follow the fate of neurons committed to a TrkC lineage and observed that they are specifically protected from NT-3 mediated apoptosis in NT-3/TrkC double knock-out embryos. Finally, using a chicken model we demonstrated that silencing NT-3 emanating from the ventral neural tube induced apoptosis in the DRG anlage. This apoptosis was inhibited by silencing TrkC. This work thus demonstrates that, during in vivo DRG development, TrkC behaves as a two-sided receptor transducing positive signals of neuronal survival in response to NT-3, but actively inducing neuronal cell death when unbound. This functional duality sets adequate number of neurons committed to a TrkC identity in the forming DRG.

Depresioaren teoria neuroinflamatorioa

Depresio nagusia asaldura neuropsikiatriko ohikoenen artean dago. Gaixotasun mental honen etiologia eta oinarri fisiopatologikoak azaltzeko hainbat teoria proposatu dira, hala nola teoría monoaminergikoa edo neurotrofikoa. Hala ere, oinarri neurobiologikoak oraindik ez dira ezagutzen, sistema ezberdinen parte-hartzea izanik proposatzen dena. Depresioan hanturaren eta funtzio neuralaren arteko elkarrekintza dagoela frogatzen duten entsegu prekliniko eta klinikoetako emaitzak gero eta pisu handiagoa hartzen ari dira, teoría neuroinflamatorioa indartuz. Horrek proposatzen du depresioan sistema ezberdinetan asaldurak gertatuko liratekeela: ardatz hipotalamiko-hipofisiario-adrenalaren (HPA) hiperaktibazioa (igotako glukokortikoide-mailak eraginez) bai eta sistema immunearen hiperaktibazioa ere, periferiako eta nerbio-sistema zentraleko (NSZ) hanturaren markatzaileen, hau da, zitokina proinflamatorioen mailak handituz. Gainera, depresiodun pazienteetan aurkitu diren periferiako gehiegizko zitokinak garunera igarotzeko gai direla eta depresioan ezagunak diren bide fisiopatologiko gehienei eragiten dietela deskribatu da. Horien artean neurotransmisoreen metabolismoa, funtzio neuroendokrinoa eta plastikotasun edo moldatze neurala daude. Hain zuzen ere, garuneko hanturaren aktibazioak depresioan gertatzen diren asaldura fisiopatologikoen antzeko moldaketak eragiten ditu, faktore neurotrofikoen gutxipena, eszitotoxikotasuna eta horren ondorio den estres oxidatiboa, adibidez. Areagotutako zitokinen kalte kronikoak iraupen luzeko aldaketak dakartza garunaren anatomian eta funtzionamenduan, eta kalteok umorean, kognizioan edo portaeran eragin zuzena izango dute. Hortaz, garunaren endekapen hau sintoma depresiboekin lotzea funtsezkoa da tratamendua aukeratzeko orduan. Izan ere, gaixotasun inflamatorioak dituzten pazienteetan lortutako emaitzen arabera, zitokina proinflamatorioak inhibitzeak gaixoek pairatzen dituzten sintoma depresiboak hobetzen eta pazientearen ohiko tratamendu antidepresiboaren erantzuna hobetzen lagundu dezake. Beraz, garunean gertatzen den hantura eta sistema immunea itu dituzten tratamenduak garatzea aukera bat izan daiteke hantura duten depresiodun pazienteen sintomatologia hobetzeko.

Genotrophic effect of neurotrophins – Restart of β-cell regeneration in diabetes mellitus

Type 2 diabetes mellitus is an epidemic worldwide and a proved risk factor for cardiovascular complications. In 89% of the cases, it deals, in fact, with metabolic syndrome of multifactorial etiopathogenesis. This paradigm has been generalized by the neurotrophic theory emphasizing the role of hyponeurotrophinemia of key factor. Both type 2 diabetes mellitus and metabolic syndrome are characterized by insulin resistance and pancreatic β-cell damage. Cyclic keeping the fast enhances plasma neurotrophin levels. Fasting induces prenatal-development gene expression in adult pancreas and promotes neurogenin (Ngn)-3 gene expression to generate insulin producing β-cells. Probably, the increased plasma and tissue levels of the nerve growth factor and brain-derived neurotrophic factor after fasting reprogramme Ngn-3 gene expression as this genotrophic action enhances Ngn-3 protein synthesis. This results in regeneration of damaged pancreatic β-cells and restores insulin secretion in type 1 and type 2 diabetes mellitus.

Pathophysiological explanation of cardiovascular benefits of sodium-glucose cotransporter-2 inhibitors by neurotrophic theory

Pathophysiological explanation of cardiovascular benefits of sodium-glucose cotransporter-2 inhibitors by neurotrophic theory

Regulation of Autocrine Signaling in Subsets of Sympathetic Neurons Has Regional Effects on Tissue Innervation.

SummaryThe regulation of innervation by target-derived factors like nerve growth factor (NGF) is the cornerstone of neurotrophic theory. Whereas autocrine signaling in neurons affecting survival and axon growth has been described, it is difficult to reconcile autocrine signaling with the idea that targets control their innervation. Here, we report that an autocrine signaling loop in developing mouse sympathetic neurons involving CD40L (TNFSF5) and CD40 (TNFRSF5) selectively enhances NGF-promoted axon growth and branching, but not survival, via CD40L reverse signaling. Because NGF negatively regulates CD40L and CD40 expression, this signaling loop operates only in neurons exposed to low levels of NGF. Consequently, the sympathetic innervation density of tissues expressing low NGF is significantly reduced in CD40-deficient mice, whereas the innervation density of tissues expressing high levels of NGF is unaffected. Our findings reveal how differential regulation of autocrine signaling in neurons has region-specific effects on axon growth and tissue innervation.

Metabolic syndrome – From the neurotrophic hypothesis to a theory

Metabolic syndrome (MetS) is a complex and heterogeneous disease characterized by central obesity, impaired glucose metabolism, dyslipidemia, arterial hypertension, insulin resistance and high-sensitivity C-reactive protein. In 2006, a neurotrophic hypothesis of the etiopathogenesis of MetS was launched. This hypothesis considered the neurotrophins a key factor in MetS development. Chronic inflammatory and/or psychoemotional distress provoke a series of neuroimmunoendocrine interactions such as increased tissue and plasma levels of proinflammatory cytokines and neurotrophins, vegetodystonia, disbalance of neurotransmitters, hormones and immunity markers, activation of the hypothalamo-pituitary-adrenal axis, insulin resistance, and atherosclerosis. An early and a late clinical stage in the course of MetS are defined. Meanwhile, evidence of supporting results from the world literature accumulates. This enables the transformation of the definition of the neurotrophic hypothesis into a neurotrophic theory of MetS. The important role of two neurotrophic factors, i.e. the nerve growth factor and brain-derived neurotrophic factor as well as of the proinflammatory cytokines, neurotransmitters, adipokines and, especially, of leptin for the development of MetS, obesity and type 2 diabetes mellitus is illustrated. There are reliable scientific arguments that the metabotrophic deficit due to reduced neurotrophins could be implicated in the pathogenesis of MetS, type 2 diabetes mellitus, and atherosclerosis as well. A special attention is paid to the activity of the hypothalamo-pituitary-adrenal axis after stress. The application of the neurotrophic theory of MetS could contribute to the etiological diagnosis and individualized management of MetS by eliminating the chronic distress, hyponeurotrophinemia and consequent pathology. It helps estimating the risk, defining the prognosis and implementing the effective prevention of this socially significant disease as evidenced by the dramatic recent growth of the world publication output on this interdisciplinary topic.

Selective regulation of nerve growth factor expression in developing cutaneous tissue by early sensory innervation

BackgroundIn the developing vertebrate peripheral nervous system, the survival of sympathetic neurons and the majority of sensory neurons depends on a supply of nerve growth factor (NGF) from tissues they innervate. Although neurotrophic theory presupposes, and the available evidence suggests, that the level of NGF expression is completely independent of innervation, the possibility that innervation may regulate the timing or level of NGF expression has not been rigorously investigated in a sufficiently well-characterized developing system.ResultsTo address this important question, we studied the influence of innervation on the regulation of NGF mRNA expression in the embryonic mouse maxillary process in vitro and in vivo. The maxillary process receives its innervation from predominantly NGF-dependent sensory neurons of the trigeminal ganglion and is the most densely innervated cutaneous territory with the highest levels of NGF in the embryo. When early, uninnervated maxillary processes were cultured alone, the level of NGF mRNA rose more slowly than in maxillary processes cultured with attached trigeminal ganglia. In contrast to the positive influence of early innervation on NGF mRNA expression, the levels of brain-derived neurotrophic factor (BDNF) mRNA and neurotrophin-3 (NT3) mRNA rose to the same extent in early maxillary processes grown with and without trigeminal ganglia. The level of NGF mRNA, but not BDNF mRNA or NT3 mRNA, was also significantly lower in the maxillary processes of erbB3-/- mice, which have substantially fewer trigeminal neurons than wild-type mice.ConclusionsThis selective effect of initial innervation on target field NGF mRNA expression provokes a re-evaluation of a key assertion of neurotrophic theory that the level of NGF expression is independent of innervation.

A Conversation with Rita Levi-Montalcini

There are very few proven theories that exist in biology. One that has stood the test of time is the neurotrophic theory. It explains why only half of the neurons produced early in development are needed to form a functional nervous system. The explanation came from the discovery of nerve growth factors (NGFs), which help nourish neurons, guide their axons to their proper connections, and prevent cell death. Rita Levi-Montalcini, who formulated this idea, celebrated her 100th birthday on April 22, 2009 in Rome. I had the opportunity to interview her at the European Brain Research Institute (EBRI) in September 2008, which forms the basis of this article. Shortly after the interview, Rita attended the International NGF meeting, held in the Upper Galilee region of Israel (Kfar Blum, Israel). Despite her age, she traveled to the meeting by flying to Tel Aviv and taking a 4-h car ride to the conference site. Remarkably, she participated in the meeting by giving a 30-min talk and sponsoring a poster (see Figure 1 ).

S4. Neurotrophic factors in autonomic nervous system development: S4.1 Novel regulators of sympathetic innervation in the developing mouse

Nerve growth factor (NGF) is the paradigmatic target-derived neurotrophic factor on which the foundations of neurotrophic theory are based. Sympathetic neurons depend for survival on a supply of NGF synthesized by their targets and conveyed to their cell soma by retrograde axonal transport. The limiting supply of target-derived NGF not only governs the number of sympathetic neurons that survive during development, it also plays an essential role in promoting the growth and branching of the axon terminals of these neurons within their distal targets.

Neurotrophic Modulation of Motor Neuron Development

Neurotrophic factors (NTFs) are a pleiotropic group of secreted growth factors that regulate multiple aspects of neuronal development, including the regressive event of cell death. Skeletal muscleinnervating lower motoneurons (MNs) of the brain stem and spinal cord comprise one population of central neurons in which programmed cell death (PCD) during embryogenesis has been actively investigated, as much for reasons of technical facility as clinical relevance. The precise identity of NTF-dependent MNs has remained unclear, with most studies simply reporting losses or gains across the entire spinal cord or individual brain-stem nuclei. However, MNs are grouped into highly heterogenous populations based on transcriptional identity, target innervation, and physiological function. Therefore, recent work has focused on the effects of NTF overexpression or deletion on the survival of these MN subpopulations. Together with the recent progress attained in the generation of conditional mutant mice, in which the function of an NTF or its receptor can be eliminated specifically in MNs, these recent studies have begun to define the differential trophic requirements for MN subpopulations during PCD. The intent of this review is to summarize these recent findings and to discuss their significance with respect to neurotrophic theory.

The Denervated Muscle: 45 years later

Forty-five years after its publication, Ernest Gutmann's book, The Denervated Muscle, still stands as a landmark publication. It summarized the state of knowledge of the time and introduced many new researches that were continuing at the Institute of Physiology in Prague. At the time, the response of a muscle to denervation was viewed primarily through the lens of the neurotrophic theory. Advancements in our understanding of neurotrophic effects and mechanisms would now call into question some of the hypotheses and interpretations presented in the book, but many of the research findings have stood the test of time. This review will cover some of the questions asked and data presented in this book, and will place them into the context of contemporary muscle biology.

Charcot neuro-osteoarthropathy

The classical neurotraumatic and neurotrophic theories for the pathogenesis of the acute Charcot neuro-osteoarthropathy (CN) in diabetes, do not address certain key features of the disease. These features include the facts that the condition usually affects just one side, that it is self-limiting, and that it is also very uncommon. Similarly, it is not known to what extent the condition may depend, as suggested by Jean-Martin Charcot, on pre-morbid osteopenia. Recent advances in understanding the mechanisms underlying the pathogenesis of osteopenia and osteoporosis and the central role of the RANKL/OPG signalling system have, however, suggested the possible involvement of other factors in the evolution of the disease. Specifically, it has been suggested that acute CN may be triggered in a susceptible individual by any event that leads to localized inflammation in the affected foot. This local inflammation leads to a vicious cycle in which there is increasing inflammation, increasing expression of RANKL, and increasing bone breakdown. The likely central role for the RANKL/OPG pathway suggests new possibilities for future treatments.