Rapid eye movement sleep deprivation increases chloride-sensitive Mg-ATPase activity in the rat brain

Rapid eye movement sleep deprivation is known to affect central neuronal excitability and responsiveness. Because chloride-sensitive Mg-ATPase is known to affect the neuronal transmembrane potential, this study was conducted to investigate if the enzyme activity might be affected on deprivation. The flower pot method was used for 2 and 4 days of deprivation and suitable control experiments were conducted. The enzyme activity was estimated in the microsomal preparation of the whole brain as well as in different areas of the brain in rats. The results suggested that the deprivation increased the enzyme activity although the chloride-insensitive Mg-ATPase activity remained unaffected. The increase in the enzyme activity is likelyto reduce the neuronal hyperpolarization. The findings fit in with existing knowledge and help in explaining earlier observations

Rapid eye movement sleep and significance of its deprivation studies - a review

Rapid eye movement (REM) sleep is a unique phenomenon within sleep-wakefulness cycle. It is associated with increased activity in certain group of neurons and decreased activity in certain other group of neurons and dreaming. It is likely to have evolved about 140 million years ago. Although mention of this stage can be traced back to as early as 11 century BC in the Hindu Vedic literature, the Upanishads, it has been defined in its present form in the mid-twentieth century. So far, neurobiology of its genesis, physiology and functional significance are not known satisfactorily and mostly remains hypothetical. Nevertheless, more and more studies have increasingly convinced us to accept that it is an important physiological phenomenon which cannot be ignored as a vestigial phenomenon. Although there are articles where different aspects of REM sleep have been dealt with, a review where the knowledge gathered by REM sleep deprivation studies to un-derstand its significance is lacking. There is a need for such a review because a major portion of the knowledge about various aspects of REM sleep, specially its functional significance, has been acquired mostly from the REM sleep deprivation studies. Hence, in this review the knowledge gathered by REM sleep deprivation studies have been cola-ted along with their importance so that it may be useful and referred to for information as well as while designing future studies

Exenatide Modulates Neuronal Insulin Signalling in Parkinson’s Disease

Objective: To further explore the mechanism of action of exenatide, a glucagon-like peptide-1 agonist, underlying the positive effects on motor function in a recently reported in a clinical trial of Parkinson’s disease.Background: Exenatide, a glucagon-like peptide-1 agonist licensed for the treatment of Type 2 diabetes was recently found to have beneficial effects on motor function in a placebo-controlled trial in patients with moderate stage Parkinson’s disease (PD). Accumulating evidence suggests that impaired insulin and Akt signalling with consequent relative deactivation of cell survival pathways play a role in PD pathogenesis.Design/Methods: We isolated serum extracellular vesicles (EVs) enriched for neuronal origin from trial participants and measuring concentrations of total and phosphorylated signalling proteins at various timepoints.Neuronal insulin receptor mediated downstream signalling cascades were investigated by measuring levels of IRS-1 proteins, whereas evidence of potential Akt and MAPK pathway activation was determined by measurement of total and phosphorylated forms of key kinases Akt, mTOR, GSK-3B, p38, Erk1/2 and JNK.Results: We found that, compared to placebo, peripherally administered exenatide can engage neuronal signalling pathways and promote activating phosphorylations on IRS-1 tyrosine residues and downstream substrates including Akt and mechanistic target of rapamycin (mTOR). Furthermore, the beneficial clinical effects of exenatide on motor function were associated with EV biomarker changes suggesting a reduction in neuronal insulin resistance and concomitant activation of mTOR signallingConclusions: The results suggest target engagement of insulin/Akt/mTOR signalling pathways in neurons by exenatide and provide a mechanistic context for the recent clinical findings of the trial

Insulin resistance and exendin-4 treatment for multiple system atrophy.

International audienceMultiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of α-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimer's disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between α-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the glucagon-like peptide-1 analogue exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric α-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with glucagon-like peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the glucagon-like peptide-1 agonist exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial

Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease

Importance: Exenatide, a glucagon-like peptide 1 agonist used in type 2 diabetes, was recently found to have beneficial effects on motor function in a randomized, placebo-controlled trial in Parkinson disease (PD). Accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling play a role in PD pathogenesis; however, exploring the extent to which drugs engage with putative mechnisms in vivo remains a challenge. Objective: To assess whether participants in the Exenatide-PD trial have augmented activity in brain insulin and Akt signaling pathways. Design, Setting, and Participants: Serum samples were collected from 60 participants in the single-center Exenatide-PD trial (June 18, 2014, to June 16, 2016), which compared patients with moderate PD randomized to 2 mg of exenatide once weekly or placebo for 48 weeks followed by a 12-week washout period. Serum extracellular vesicles, including exosomes, were extracted, precipitated, and enriched for neuronal source by anti–L1 cell adhesion molecule antibody absorption, and proteins of interest were evaluated using electrochemiluminescence assays. Statistical analysis was performed from May 1, 2017, to August 31, 2017. Main Outcomes and Measures: The main outcome was augmented brain insulin signaling that manifested as a change in tyrosine phosphorylated insulin receptor substrate 1 within neuronal extracellular vesicles at the end of 48 weeks of exenatide treatment. Additional outcome measures were changes in other insulin receptor substrate proteins and effects on protein expression in the Akt and mitogen-activated protein kinase pathways. Results: Sixty patients (mean [SD] age, 59.9 [8.4] years; 43 [72%] male) participated in the study: 31 in the exenatide group and 29 in the placebo group (data from 1 patient in the exenatide group were excluded). Patients treated with exenatide had augmented tyrosine phosphorylation of insulin receptor substrate 1 at 48 weeks (0.27 absorbance units [AU]; 95% CI, 0.09-0.44 AU; P = .003) and 60 weeks (0.23 AU; 95% CI, 0.05-0.41 AU; P = .01) compared with patients receiving placebo. Exenatide-treated patients had elevated expression of downstream substrates, including total Akt (0.35 U/mL; 95% CI, 0.16-0.53 U/mL; P < .001) and phosphorylated mechanistic target of rapamycin (mTOR) (0.22 AU; 95% CI, 0.04-0.40 AU; P = .02). Improvements in Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 off-medication scores were associated with levels of total mTOR (F4,50 = 5.343, P = .001) and phosphorylated mTOR (F4,50 = 4.384, P = .04). Conclusions and Relevance: The results of this study are consistent with target engagement of brain insulin, Akt, and mTOR signaling pathways by exenatide and provide a mechanistic context for the clinical findings of the Exenatide-PD trial. This study suggests the potential of using exosome-based biomarkers as objective measures of target engagement in clinical trials using drugs that target neuronal pathways