https://repositorio.uca.edu.ar/bitstream/123456789/1653/1/melatonin-pleiotropic-orchestrating-regulator-molecule.pdf

Melatonin—A pleiotropic, orchestrating regulator molecule

Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products.

The close, bidirectional relationship between depression and cardiovascular disease is well established. Major depression is associated with an increased risk of coronary artery disease and acute cardiovascular sequelae, such as myocardial infarction, congestive heart failure, and isolated systolic hypertension. Morbidity and mortality in patients with cardiovascular disease and depression are significantly higher than in patients with cardiovascular disease who are not depressed. Various pathophysiological mechanisms might underlie the risk of cardiovascular disease in patients with depression: increased inflammation; increased susceptibility to blood clotting (owing to alterations in multiple steps of the clotting cascade, including platelet activation and aggregation); oxidative stress; subclinical hypothyroidism; hyperactivity of the sympatho-adrenomedullary system and the hypothalamic-pituitary-adrenal axis; reductions in numbers of circulating endothelial progenitor cells and associated arterial repair processes; decreased heart rate variability; and the presence of genetic factors. Early identification of patients with depression who are at risk of cardiovascular disease, as well as prevention and appropriate treatment of cardiovascular disease in these patients, is an important and attainable goal. However, adequately powered studies are required to determine the optimal treatment regimen for patients with both depression and cardiovascular disorders.

Heartache and heartbreak—the link between depression and cardiovascular disease

Perineuronal nets (PNNs) are unique extracellular matrix structures that wrap around certain neurons in the CNS during development and control plasticity in the adult CNS. They appear to contribute to a wide range of diseases/disorders of the brain, are involved in recovery from spinal cord injury, and are altered during aging, learning and memory, and after exposure to drugs of abuse. Here the focus is on how a major component of PNNs, chondroitin sulfate proteoglycans, control plasticity, and on the role of PNNs in memory in normal aging, in a tauopathy model of Alzheimer's disease, and in drug addiction. Also discussed is how altered extracellular matrix/PNN formation during development may produce synaptic pathology associated with schizophrenia, bipolar disorder, major depression, and autism spectrum disorders. Understanding the molecular underpinnings of how PNNs are altered in normal physiology and disease will offer insights into new treatment approaches for these diseases.

https://www.jneurosci.org/content/jneuro/36/45/11459.full.pdf

Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity.

Activity-dependent changes in neuronal gene expression require a means of synapse-to-nucleus signalling, and changes in nuclear calcium concentration provide a major route for such communication. Bading discusses how nuclear calcium signals are induced by synaptic activity and describes their role as regulators of gene expression in neuroadaptations.

http://www.uni-heidelberg.de/md/nbio/teaching/bading2013.pdf

Nuclear calcium signalling in the regulation of brain function

Brain biomarkers for identifying excited delirium as a cause of sudden death.

The chronic effects of cocaine abuse on brain structure and function are blamed for the inability of most addicts to remain abstinent. Part of the difficulty in preventing relapse is the persisting memory of the intense euphoria or cocaine "rush". Most abused drugs and alcohol induce neuroplastic changes in brain pathways subserving emotion and cognition. Such changes may account for the consolidation and structural reconfiguration of synaptic connections with exposure to cocaine. Adaptive hippocampal plasticity could be related to specific patterns of gene expression with chronic cocaine abuse. Here, we compare gene expression profiles in the human hippocampus from cocaine addicts and age-matched drug-free control subjects. Cocaine abusers had 151 gene transcripts upregulated, while 91 gene transcripts were downregulated. Topping the list of cocaine-regulated transcripts was RECK in the human hippocampus (FC = 2.0; p<0.05). RECK is a membrane-anchored MMP inhibitor that is implicated in the coordinated regulation of extracellular matrix integrity and angiogenesis. In keeping with elevated RECK expression, active MMP9 protein levels were decreased in the hippocampus from cocaine abusers. Pathway analysis identified other genes regulated by cocaine that code for proteins involved in the remodeling of the cytomatrix and synaptic connections and the inhibition of blood vessel proliferation (PCDH8, LAMB1, ITGB6, CTGF and EphB4). The observed microarray phenotype in the human hippocampus identified RECK and other region-specific genes that may promote long-lasting structural changes with repeated cocaine abuse. Extracellular matrix remodeling in the hippocampus may be a persisting effect of chronic abuse that contributes to the compulsive and relapsing nature of cocaine addiction.

/pdf/gene-expression-in-human-hippocampus-from-cocaine-abusers-316netjwuc.pdf

Gene Expression in Human Hippocampus from Cocaine Abusers Identifies Genes which Regulate Extracellular Matrix Remodeling

BACKGROUND Idiopathic Parkinson disease (PD) is a multi-system disorder with a multifactorial etiology and diverse clinical phenotype. Selective, regional dopaminergic neuronal degeneration in the substantia nigra and other CNS areas including the amygdala are observed in all patients. Apoptotic mechanisms resulting from oxidative stress and mitochondrial dysfunction have been implicated in the pathogenesis of the disease. Although the role of melatonin, a potent endogenous antioxidant, has been highlighted in PD there is no data on the expression of melatonin receptors in affected CNS regions. MATERIAL/METHODS We conducted an RT-PCR-based study to determine the MT1 and MT2 receptors expression in whole brain post-mortem tissue from the amygdala and substantia nigra of well-characterized PD and control subjects. RESULTS PD cases showed a statistically significant decrease of MT1 receptor expression in both substantia nigra (FC=5.11; p<0.05) and the amygdala (FC=3.11; p<0.001) versus normal controls. The expression of MT2 receptor expression was also decreased in both substantia nigra (FC=3.90; p<0.0001) and the amygdala (FC=1.91; p<0.001) versus normal controls. CONCLUSIONS The results demonstrate a down-regulation of melatonin receptors in regions affected by PD, suggesting their possible involvement in the disease process. Future studies are needed to elucidate the role of melatonin and its receptors in the treatment/pathogenesis of PD.

Melatonin MT1 and MT2 receptor expression in Parkinson's disease.

Background: Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. Most cases are sporadic but about 10–15% of patients have a positive family history of PD

A prospective study of familial versus sporadic Parkinson's disease.

In Parkinson's disease (PD) neuronal degeneration is associated with abnormal protein aggregation in various forms including Lewy bodies (LBs). A major component of LBs is alpha-synuclein; septin 4 (SEPT4), a polymerizing GTP-binding protein that serves as scaffold for diverse molecules has been found to colocalize with alpha-synuclein in LBs. The central role of SEPT4 in the etiopathogenesis of PD has been suggested since SEPT4 also shows a physiological association with alpha-synuclein and serves as a substrate for parkin. To this end, we studied the expression of septin 4 and alpha-synuclein in postmortem human substantia nigra (SN) and amygdala from patients with PD and healthy controls. Twenty patients (14 men : 6 women, onset 63.0 +/- 11.4 years, age 77.3 +/- 7.6 years, Hoehn and Yahr 4.05/5) and 9 neurologically healthy controls (4 men/5 women, age at death 80.1 +/- 8.6 years) were studied. Sporadic PD cases showed a statistically significant decrease of the fold change (FC) of SNCA (FC = 0.31, P = 0.00001) and SEPT4 (FC = 0.67, P = 0.054) gene expressions in the SN and the amygdala (SNCA: FC = 0.49, P = 0.02; SEPT4: FC = 0.32, P = 0.007) versus healthy controls. However, an increase of both proteins in PD versus control subjects was observed with immunoblotting. The semi-quantitative protein ratio calculations revealed more than 10-fold increases for both SEPT4 and alpha-synuclein in PD versus control subjects. We present for the first time similar signal expression patterns and parallel accumulation of SEPT4 and alpha-synuclein in well-characterized postmortem PD brain. Considering the heterogeneous etiology of sporadic PD and the variability of individual human samples, SEPT4 accumulation may be regarded as one of the common pathological changes in PD and should therefore be further explored.

Nikhil Adi

Papers

Brain biomarkers for identifying excited delirium as a cause of sudden death.

Gene Expression in Human Hippocampus from Cocaine Abusers Identifies Genes which Regulate Extracellular Matrix Remodeling

Melatonin MT1 and MT2 receptor expression in Parkinson's disease.

A prospective study of familial versus sporadic Parkinson's disease.

Expression of Lewy body protein septin 4 in postmortem brain of Parkinson's disease and control subjects.