The expression of agmatinase manipulates the affective state of rats subjected to chronic restraint stress.

Agmatine is an endogenous polyamine produced from l-arginine and degraded by agmatinase (AGMAT). Studies in humans and animals have shown that agmatine has neuroprotective, anxiolytic, and antidepressant-like actions. However, little is known about the role of AGMAT in the action of agmatine or in the pathophysiology of psychiatric disorders. Therefore, this study aimed to investigate the role of AGMAT in the pathophysiology of MDD. In this study, we observed that AGMAT expression increased in the ventral hippocampus rather than in the medial prefrontal cortex in the chronic restraint stress (CRS) animal model of depression. Furthermore, we found that AGMAT overexpression in the ventral hippocampus elicited depressive- and anxiety-like behaviors, whereas knockdown of AGMAT exhibited antidepressant and anxiolytic effects in CRS animals. Field and whole-cell recordings of hippocampal CA1 revealed that AGMAT blockage increased Schaffer collateral-CA1 excitatory synaptic transmission, which was expressed both pre- and post-synaptically and was probably due to the inhibition of AGMAT-expressing local interneurons. Therefore, our results suggest that dysregulation of AGMAT is involved in the pathophysiology of depression and is a potential target for designing more effective antidepressants with fewer adverse effects to offer a better therapy for depression.

Exercise postconditioning reduces ischemic injury via suppression of cerebral gluconeogenesis in rats.

Pre-stroke exercise conditioning reduces neurovascular injury and improves functional outcomes after stroke. The goal of this study was to explore if post-stroke exercise conditioning (PostE) reduced brain injury and whether it was associated with the regulation of gluconeogenesis. Adult rats received 2 h of middle cerebral artery (MCA) occlusion, followed by 24 h of reperfusion. Treadmill activity was then initiated 24 h after reperfusion for PostE. The severity of the brain damage was determined by infarct volume, apoptotic cell death, and neurological deficit at one and three days after reperfusion. We measured gluconeogenesis including oxaloacetate (OAA), phosphoenolpyruvate (PEP), pyruvic acid, lactate, ROS, and glucose via ELISA, as well as the location and expression of the key enzyme phosphoenolpyruvate carboxykinase (PCK)-1/2 via immunofluorescence. We also determined upstream pathways including forkhead transcription factor (FoxO1), p-FoxO1, 3-kinase (PI3K)/Akt, and p-PI3K/Akt via Western blot. Additionally, the cytoplasmic expression of p-FoxO1 was detected by immunofluorescence. Compared to non-exercise control, PostE (*p < .05) decreased brain infarct volumes, neurological deficits, and cell death at one and three days. PostE groups (*p < .05) saw increases in OAA and decreases in PEP, pyruvic acid, lactate, ROS, glucose levels, and tissue PCKs expression on both days. PCK-1/2 expressions were also significantly (*p < .05) suppressed by the exercise setting. Additionally, phosphorylated PI3K, AKT, and FoxO1 protein expression were significantly induced by PostE at one and three days (*p < .05). In this study, PostE reduced brain injury after stroke, in association with activated PI3K/AKT/FoxO1 signaling, and inhibited gluconeogenesis. These results suggest the involvement of FoxO1 regulation of gluconeogenesis underlying post-stroke neuroprotection.

Accumulation of formaldehyde causes motor deficits in an in vivo model of hindlimb unloading.

During duration spaceflight, or after their return to earth, astronauts have often suffered from gait instability and cerebellar ataxia. Here, we use a mouse model of hindlimb unloading (HU) to explore a mechanism of how reduced hindlimb burden may contribute to motor deficits. The results showed that these mice which have experienced HU for 2 weeks exhibit a rapid accumulation of formaldehyde in the gastrocnemius muscle and fastigial nucleus of cerebellum. The activation of semicarbazide-sensitive amine oxidase and sarcosine dehydrogenase induced by HU-stress contributed to formaldehyde generation and loss of the abilities to maintain balance and coordinate motor activities. Further, knockout of formaldehyde dehydrogenase (FDH-/-) in mice caused formaldehyde accumulation in the muscle and cerebellum that was associated with motor deficits. Remarkably, formaldehyde injection into the gastrocnemius muscle led to gait instability; especially, microinfusion of formaldehyde into the fastigial nucleus directly induced the same symptoms as HU-induced acute ataxia. Hence, excessive formaldehyde damages motor functions of the muscle and cerebellum.

A rapid and non-invasive fluorescence method for quantifying coenzyme Q10 in blood and urine in clinical analysis.

BACKGROUND: Coenzyme Q10 (CoQ10) supplementation can improve cognition in patients with Alzheimer's disease (AD) and AD transgenic model mice. To ameliorate the discomfort that patients with AD suffer after several blood extractions, a non-invasive method for detecting urine CoQ10 levels needs to be established. METHODS: Here, we developed a new technique of fluorescence spectrophotometry with ethyl cyanoacetate (FS-ECA), on the basis of the principle that the chemical derivative obtained from the interaction between CoQ10 and ECA was detected by a fluorescence detector at λex/em  = 450/515 nm. As a standard reference method, the same batches of the clinical samples were analyzed by high-performance liquid chromatography with an ultraviolet detector (HPLC-UV) at 275 nm. RESULTS: The limits of detection (LOD) and limits of quantization (LOQ) (serum: 0.021 and 0.043 mg/L; urine: 0.012 and 0.025 mg/L) determined by the FS-ECA method were similar to that obtained through HPLC-UV (serum: 0.017 and 0.035 mg/L; urine: 0.012 and 0.025 mg/L). More importantly, this new FS-ECA technique as well as the conventional HPLC-UV method could detect a marked difference in urine CoQ10 levels between AD and controls. CONCLUSION: Our findings suggest that this non-invasive method for quantifying urine CoQ10 potentially replaces HPLC to detect blood CoQ10.

Endogenous formaldehyde is a memory-related molecule in mice and humans.

Gaseous formaldehyde is an organic small molecule formed in the early stages of earth's evolution. Although toxic in high concentrations, formaldehyde plays an important role in cellular metabolism and, unexpectedly, is found even in the healthy brain. However, its pathophysiological functions in the brain are unknown. Here, we report that under physiological conditions, spatial learning activity elicits rapid formaldehyde generation from mitochondrial sarcosine dehydrogenase (SARDH). We find that elevated formaldehyde levels facilitate spatial memory formation by enhancing N-methyl-D-aspartate (NMDA) currents, but that high formaldehyde concentrations gradually inactivate the NMDA receptor by cross-linking NR1 subunits to NR2B via the C232 residue. We also report that in mice with aldehyde dehydrogenase-2 (ALDH2) knockout, formaldehyde accumulation due to hypofunctional ALDH2 impairs memory, consistent with observations of Alzheimer's disease patients. We also find that formaldehyde deficiency caused by mutation of the mitochondrial SARDH gene in children with sarcosinemia or in mice with Sardh deletion leads to cognitive deficits. Hence, we conclude that endogenous formaldehyde regulates learning and memory via the NMDA receptor.

Erratum: Publisher Correction: Endogenous formaldehyde is a memory-related molecule in mice and humans.

[This corrects the article DOI: 10.1038/s42003-019-0694-x.].