Soluble and membrane embedded neurotrophic factors bind to specific receptors on responsive neurons and thereby initiate dramatic changes in the proliferation, differentiation, and survival of their target cells. Recent studies have elucidated many of the intracellular pathways by which neurotrophins and ciliary neurotrophic factor (CNTF) function to regulate gene expression and thereby achieve diverse biological responses. In this review we have focused particular attention on the importance of the Ras-MAP kinase pathway for neurotrophin signaling, and the role of the Jak-STAT pathway for CNTF signaling. Characterization of the enzymes, linker proteins, and transcription factors that are sequentially activated in response to neurotrophic factors has provided significant insight into the mechanisms by which these agents elicit specific biological responses during normal development and into the adaptive responses of mature neurons.

Intracellular signaling pathways activated by neurotrophic factors.

MR spectroscopy is used worldwide as an adjunct to MR imaging in several common neurologic diseases, including brain neoplasms, inherited metabolic disorders, demyelinating disorders, and infective focal lesions.

/pdf/clinical-proton-mr-spectroscopy-in-central-nervous-system-4df788he1k.pdf

Clinical Proton MR Spectroscopy in Central Nervous System Disorders

Noradrenergic mechanisms in neurodegenerative diseases: a theory.

Although neurotrophins have traditionally been regarded as neuronal survival factors, recent work has suggested a role for these factors in synaptic plasticity. In particular, brain-derived neurotrophic factor (BDNF) rapidly enhances synaptic transmission in hippocampal neurons through trkB receptor stimulation and postsynaptic phosphorylation mechanisms. Activation of trkB also modulates hippocampal long-term potentiation, in which postsynaptic N-methyl-d-aspartate glutamate receptors play a key role. However, the final common pathway through which BDNF increases postsynaptic responsiveness is unknown. We now report that BDNF, within 5 min of exposure, elicits a dose-dependent increase in phosphorylation of the N-methyl-d-aspartate receptor subunit 1. This acute effect occurred in hippocampal synaptoneurosomes, which contain pre- and postsynaptic elements, and in isolated hippocampal postsynaptic densities. Nerve growth factor, in contrast, caused no enhancement of phosphorylation. These results suggest a potential mechanism for trophin-induced potentiation of synaptic transmission.

https://www.pnas.org/content/pnas/94/15/8191.full.pdf

Brain-derived neurotrophic factor rapidly enhances phosphorylation of the postsynaptic N-methyl-d-aspartate receptor subunit 1

Inhibitors of regeneration in myelin, such as myelin-associated glycoprotein (MAG), play an important role in preventing regeneration after CNS injury. Elevation of cAMP, either with dibutyryl-cAMP (db-cAMP) or by priming with a variety of neurotrophins, overcomes inhibition by MAG and myelin. However, activation of cAMP is not generally regarded as a signaling pathway for neurotrophins. Here we show that the NGF-like neurotrophins overcome inhibition by MAG by activating tyrosine kinase receptors. We also show that activation of extracellular signal-regulated kinase (Erk) by BDNF is required to overcome inhibition by MAG, and that activated Erk transiently inhibits phosphodiesterase 4 (PDE4), the enzyme that hydrolyzes cAMP. Inhibition of PDE4 then allows cAMP to increase and so initiates the pathway to overcome inhibition. Furthermore, we also show that basal levels of Erk activation and basal cAMP levels contribute to the effects of db-cAMP by pushing the combined levels of cAMP above a threshold required to overcome inhibition. Together, these results not only show how NGF-like neurotrophins can elevate cAMP and overcome inhibition but also point to a novel mechanism of cross talk in neurons from the Erk to the cAMP signaling pathways.

https://www.jneurosci.org/content/jneuro/23/37/11770.full.pdf

Neurotrophins elevate cAMP to reach a threshold required to overcome inhibition by MAG through extracellular signal-regulated kinase-dependent inhibition of phosphodiesterase.

The purpose of this study was to measure metabolite level changes in patients with newly diagnosed Alzheimer Disease (AD) following four months of donepezil treatment. A small number of cognitively normal elderly subjects were also scanned longitudinally (twice within one year) to assess the reproducibility. Short echo-time 1 H magnetic resonance spectra were acquired at 4.0 T in the right hippocampus. Subjects were scanned at the time of first diagnosis (prior to receiving donepezil) and then following four months of donepezil treatment (5 mg/day for the first month, 10 mg/day thereafter). Changes in absolute metabolite levels and metabolite ratios were quantified and compared. There was no change in measured cognitive function following four months of donepezil treatment in the AD patients. Decreased levels of N -acetylaspartate, choline, N -acetylaspartate/creatine, choline/creatine, and myo-inositol/creatine were observed in AD patients after four months of treatment. Cognitively normal elderly subjects showed an increase in myo-inositol/choline ratio following one year. The reduced levels of N -acetylaspartate in AD patients indicates continued decline in neuronal function and/or integrity. However decreased levels of choline and myo-inositol/creatine ratio may indicate a positive treatment effect.

High field 1H MRS of the hippocampus after donepezil treatment in Alzheimer disease

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2893%2981382-A

Neurotrophin induced cAMP and IP3 responses in PC12 cells: Different pathways

Neurotrophins (NGF, BDNF) elicit significant elevation of cAMP as well as IP3-concentrations in either membrane preparations or intact isolated nerve endings from rat brain hippocampus The induced second messenger responses in membrane preparations were detectable in the subsecond time range The IP3-level reached a maximum after a few hundred ms; whereas the cAMP-level continued to rise even after several seconds The IP3-response but not the cAMP-signal was inhibited in the presence of the tyrosine kinase blocker K252a, suggesting that the two second messenger cascades were triggered via different mechanisms The results suggest that neurotrophins may induce short-term effects in nerve terminals via second messenger pathways

Neurotrophin induced second messenger responses in rat brain synaptosomes.

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High field 1H MRS of the hippocampus after donepezil treatment in Alzheimer disease

Neurotrophin induced cAMP and IP3 responses in PC12 cells: Different pathways

Neurotrophin induced second messenger responses in rat brain synaptosomes.