Neurochemical Research

Cai, Zongyan; Han, Xue; Li, Ruizhe; Yu, Tianci; Chen, Lei; Wu, XueXue; Jin, Jiaxin

doi: 10.1007/s11064-022-03720-ypmid: 35974214

Spinal cord injury (SCI) can result in a partial or complete loss of motor and sensory function below the injured segment, which has a significant impact on patients' quality of life and places a significant social burden on them. Long non-coding RNA (LncRNA) is a 200–1000 bp non-coding RNA that has been shown to have a key regulatory role in the progression of a variety of neurological illnesses. Many studies have demonstrated that differentially expressed LncRNAs following spinal cord injury can participate in inflammatory damage, apoptosis, and nerve healing by functioning as competitive endogenous RNA (ceRNA); at the same time, it has a significant regulatory effect on sequelae such neuropathic pain. As a result, we believe that LncRNAs could be useful as a molecular regulatory target in the diagnosis, treatment, and prognosis of spinal cord injury.

Bhatia, Shiveena; Singh, Manjinder; Singh, Tanveer; Singh, Varinder

doi: 10.1007/s11064-022-03722-wpmid: 35987974

Finding an effective cure for Alzheimer’s disease has eluded scientists despite intense research. The disease is a cause of suffering for millions of people worldwide and is characterized by dementia accompanied by cognitive and motor deficits, ultimately culminating in the death of the patient. The course of the disease progression has various underlying contributing pathways, with the first and foremost factor being the development and accumulation of aberrant and misfolded proteins exhibiting neurotoxic functions. The impairment of cellular clearance mechanisms adds to their accumulation, resulting in neuronal death. This is where the PROteolysis TArgeting Chimera (PROTAC) technology comes into play, bringing the UPS degradation machinery in the proximity of the target protein for initiating its degradation and clearing abnormal protein debris with unparalleled precision demonstrating an edge over traditional protein inhibitors in many respects. The technology is widely explored in cancer research and utilized in the treatment of various tumors and malignancies, and is now being applied in treating AD. This review explores the application of PROTAC technology in developing lead compounds for managing this deadly disease along with detailing the pieces of evidence justifying its utility and efficacy.

Seyedaghamiri, Fatemehsadat; Rajabi, Mojgan; Mohaddes, Gisou

doi: 10.1007/s11064-022-03734-6pmid: 36048350

Alzheimer's disease (AD) is considered a multifactorial disease and a significant cause of dementia during aging. This neurodegenerative disease process is classically divided into two different pathologies cerebral accumulation of amyloid-β and hyperphosphorylated neurofibrillary tau tangles. In recent years, massive efforts have been made to treat AD by decreasing amyloid-β and tau in the brains of patients with AD, with no success. The dysfunction of a wide range of microRNAs promotes the generation and insufficient clearance of amyloid-β (Aβ) and increases tau plaques which are the pathophysiological markers of AD. Disturbance of these microRNAs is associated with mitochondrial dysfunction, oxidative damage, inflammation, apolipoprotein E4 (APOE4) pathogenic process, synaptic loss, and cognitive deficits induced by AD. Targeting a specific microRNA to restore AD-induced impairments at multiple stages might provide a promising approach for developing new drugs and therapeutic strategies for patients with AD. This review focuses on different mechanisms of microRNAs in AD pathophysiology.

Brockmueller, Aranka; Mahmoudi, Negin; Movaeni, Amir Kian; Mueller, Anna-Lena; Kajbafzadeh, Abdol-Mohammad; Shakibaei, Mehdi; Zolbin, Masoumeh Majidi

doi: 10.1007/s11064-022-03746-2pmid: 36112254

Neurodegenerative diseases refer to a group of neurological disorders as a consequence of various destructive illnesses, that predominantly impact neurons in the central nervous system, resulting in impairments in certain brain functions. Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and other neurodegenerative disorders represent a major risk to human health. In order to optimize structural and functional recovery, reconstructive methods integrate many approaches now, to address the complex and multivariate pathophysiology of neurodegenerative disorders. Stem cells, with their unique property of regeneration, offer new possibilities in regenerative and reconstructive medicine. Concurrently, there is an important role for natural products in controlling many health sufferings and they can delay or even prevent the onset of various diseases. In addition, due to their therapeutic properties, they have been used as neuroprotective agents to treat neurodegenerative disorders. After decades of intensive research, scientists made advances in treating these disorders so far, but current therapies are still not capable of preventing the illnesses from progressing. Therefore, in this review, we focused on a new perspective combining stem cells and natural products as an innovative therapy option in the management of neurodegenerative diseases.

Andersen, Jens V.; Westi, Emil W.; Neal, Elliott S.; Aldana, Blanca I.; Borges, Karin

doi: 10.1007/s11064-022-03726-6pmid: 35999339

Ketogenic diets and medium-chain triglycerides are gaining attention as treatment of neurological disorders. Their major metabolites, β-hydroxybutyrate (βHB) and the medium-chain fatty acids (MCFAs) octanoic acid (C8) and decanoic acid (C10), are auxiliary brain fuels. To which extent these fuels compete for metabolism in different brain cell types is unknown. Here, we used acutely isolated mouse cerebral cortical slices to (1) compare metabolism of 200 µM [U-13C]C8, [U-13C]C10 and [U-13C]βHB and (2) assess potential competition between metabolism of βHB and MCFAs by quantifying metabolite 13C enrichment using gas chromatography-mass spectrometry (GC–MS) analysis. The 13C enrichment in most metabolites was similar with [U-13C]C8 and [U-13C]C10 as substrates, but several fold lower with [U-13C]βHB. The 13C enrichment in glutamate was in a similar range for all three substrates, whereas the 13C enrichments in citrate and glutamine were markedly higher with both [U-13C]C8 and [U-13C]C10 compared with [U-13C]βHB. As citrate and glutamine are indicators of astrocytic metabolism, the results indicate active MCFA metabolism in astrocytes, while βHB is metabolized in a different cellular compartment. In competition experiments, 12C-βHB altered 13C incorporation from [U-13C]C8 and [U-13C]C10 in only a few instances, while 12C-C8 and 12C-C10 only further decreased the low [U-13C]βHB-derived 13C incorporation into citrate and glutamine, signifying little competition for oxidative metabolism between βHB and the MCFAs. Overall, the data demonstrate that βHB and MCFAs are supplementary fuels in different cellular compartments in the brain without notable competition. Thus, the use of medium-chain triglycerides in ketogenic diets is likely to be beneficial in conditions with carbon and energy shortages in both astrocytes and neurons, such as GLUT1 deficiency.

Wang, Xiaoyi; Yu, Xiaomeng; Li, Yujuan; Liu, Fengxia; Du, Liyuan; Xie, Nanchang; Wang, Cui

doi: 10.1007/s11064-022-03702-0pmid: 35939173

The mitochondrial unfolded protein response (mtUPR)-a stress response pathway for maintaining protein homeostasis-is critical in seizures-induced neuronal injury. The activating transcription factor 5 (ATF5) regulates mtUPR; however, whether ATF5-regulated mtUPR has a role in neuronal injury in epilepsy remains uncertain. Here, we investigated the effects of ATF5-regulated mtUPR on neuronal injury in hippocampal neurons with seizures evoked by Mg2+-free medium. HSP60 and ClpP, key proteins of mtUPR, were upregulated, indicating mtUPR activation. ATF5 overexpression by lentiviral vector infection potentiated mtUPR, whereas ATF5 downregulation by lentiviral vector infection attenuated this response. Moreover, ATF5 overexpression elevated mitochondrial membrane potential and reduced reactive oxygen species (ROS) generation, suggesting that ATF5 overexpression protected mitochondrial homeostasis, while ATF5 downregulation had the opposite effect. ATF5 overexpression also reversed Bcl2 downregulation and Bax upregulation and attenuated seizures-induced neuronal apoptosis, while ATF5 downregulation aggravated the injury. Our study demonstrates that ATF5 attenuates seizures-induced neuronal injury, possibly by regulating mtUPR pathways, to prevent mitochondrial dysfunction.

Cai, Aojie; Liu, Nana; Lin, Zehong; Li, Xiao; Wang, Jingmin; Wu, Ye; Gao, Kai; Jiang, Yuwu

doi: 10.1007/s11064-022-03716-8pmid: 35987975

Acitretin is an oral drug approved by the Food and Drug Administration that is commonly used to treat psoriasis. In recent years, acitretin has been identified as a candidate drug for the treatment of Alzheimer’s disease, but its role in neuronal development is still unclear. In this study, the human neuroblastoma cell line SH-SY5Y was used as a model to study neuronal differentiation. We found that acitretin effectively promoted the differentiation of SH-SY5Y cells into neuronal cells and upregulated the expression of the neuronal marker β-III tubulin and the mature neuronal marker NFH. Differentially expressed genes were identified by RNA sequencing and analyzed by bioinformatics approaches. The results showed that genes associated with neuron development-related pathways, such as SSPO and KCNT1, had significant changes in expression. Analysis showed that PRKCA and CAMK2B may play important roles in the process by which acitretin promotes neurodevelopment. Through whole-cell patch clamping and a microelectrode array assay, we found that acitretin-treated neurons generated electrical spikes similar to those generated by mature neurons. This study provided evidence to support an accessible and safe model of neuron-like cells and verified that acitretin can promote the differentiation of neurons and has the potential to treat brain tumors and neurodevelopmental and neurodegenerative diseases.

Pradhan, Lilesh Kumar; Sahoo, Pradyumna Kumar; Sarangi, Prerana; Chauhan, Nishant Ranjan; Das, Saroj Kumar

doi: 10.1007/s11064-022-03724-8pmid: 36001190

Neuropsychiatric upshots following chronic exposure to unpredictable adverse stressors have been well documented in the literature. Considering the significant impact of chronic unpredictable stress (CUS), the literature is elusive regarding the neuroprotective efficacy of taurine against CUS-induced oxidative stress and chromatin condensation in the zebrafish brain. In this study, to ameliorate CUS-persuaded neurological outcomes, waterborne treatment of taurine as a prophylactic intervention was undertaken. Further, our approach also focused on the gross neurobehavioral response of zebrafish, oxidative stress indices and neuromorphology of the zebrafish brain following CUS exposure with taurine treatment. Because taurine provides significant neuroprotection against oxidative insult, the cytosolic level of monoamine oxidase (MAO) in the zebrafish brain following CUS exposure is worth investigating. Further, as heightened MAO activity is associated with augmented oxidative and chromatin condensation, the focus of this study was on whether taurine provides neuroprotection by downregulating MAO levels in the brain. Our findings show that CUS-persuaded altered neurobehavioral response was significantly rescued by taurine. Moreover, our findings firmly support the hypothesis that taurine acts as a radical neuroprotector by restoring glutathione biosynthesis in the zebrafish brain subsequent to CUS exposure. Additionally, the rising level of brain MAO following chronic exposure to CUS is ameliorated by taurine treatment. These findings strongly advocate the role of taurine as a natural MAO inhibitor through the neuroprotection it provides against CUS-instigated oxidative stress in zebrafish. However, the fundamental neuroprotective mechanism of such natural compounds needs to be elucidated to determine their neuroprotective efficacy against stress regimens.

Ojo, Olubukola Benedicta; Amoo, Zainab Abiola; Olaleye, Mary Tolulope; Jha, Sushil Kumar; Akinmoladun, Afolabi Clement

doi: 10.1007/s11064-022-03732-8pmid: 36006597

Strict metabolic regulation in discrete brain regions leads to neurochemical changes in cerebral ischemia. Accumulation of extracellular glutamate is one of the early neurochemical changes that take place during cerebral ischemia. Understanding the sequential neurochemical processes involved in cerebral ischemia-mediated excitotoxicity before the clinical intervention of revascularization and reperfusion may greatly influence future therapeutic strategies for clinical stroke recovery. This study investigated the influence of time and brain regions on excitatory neurochemical indices in the bilateral common carotid artery occlusion (BCCAO) model of global ischemia. Male Wistar rats were subjected to BCCAO for 15 and 60 min to evaluate the effect of ischemia duration on excitatory neurochemical indices (dopamine level, glutamine synthetase, glutaminase, glutamate dehydrogenase, aspartate aminotransferase, monoamine oxidase, acetylcholinesterase, and Na+ K+ ATPase activities) in the discrete brain regions (cortex, striatum, cerebellum, and hippocampus). BCCAO without reperfusion caused marked time and brain region-dependent alterations in glutamatergic, glutaminergic, dopaminergic, monoaminergic, cholinergic, and electrogenic homeostasis. Prolonged BCCAO decreased cortical, striatal, and cerebellar glutamatergic, glutaminergic, dopaminergic, cholinergic, and electrogenic activities; increased hippocampal glutamatergic, glutaminergic, dopaminergic, and cholinergic activities, increased cortical and striatal monoaminergic activity; decreased cerebellar and hippocampal monoaminergic activity; and decreased hippocampal electrogenic activity. This suggests that excitatory neurotransmitters play a major role in the tissue-specific metabolic plasticity and reprogramming that takes place between the onset of cardiac arrest-mediated global ischemia and clinical intervention of recanalization. These tissue-specific neurochemical indices may serve as diagnostic and therapeutic strategies for mitigating the progression of ischemic damage before revascularization.

da Silva, Thayanara Cruz; da Silveira, Tássia Limana; dos Santos, Luiza Venturini; Arantes, Leticia Priscila; Martins, Rodrigo Pereira; Soares, Félix Alexandre Antunes; Dalla Corte, Cristiane Lenz

doi: 10.1007/s11064-022-03727-5pmid: 36018438

Adenosine, a purine nucleoside with neuromodulatory actions, is part of the purinergic signaling system (PSS). Caenorhabditis elegans is a free-living nematode found in soil, used in biological research for its advantages as an alternative experimental model. Since there is a lack of evidence of adenosine’s direct actions and the PSS’s participation in this animal, such an investigation is necessary. In this research, we aimed to test the effects of acute and chronic adenosine at 1, 5, and 10 mM on nematode’s behaviors, morphology, survival after stress conditions, and on pathways related to the response to oxidative stress (DAF-16/FOXO and SKN-1) and genes products downstream these pathways (SOD-3, HSP-16.2, and GCS-1). Acute or chronic adenosine did not alter the worms’ morphology analyzed by the worms’ length, width, and area, nor interfered with reproductive behavior. On the other hand, acute and chronic adenosine modulated the defecation rate, pharyngeal pumping rate, and locomotion, in addition, to interacting with stress response pathways in C. elegans. Adenosine interfered in the speed and mobility of the worms analyzed. In addition, both acute and chronic adenosine presented modulatory effects on oxidative stress response signaling. Acute adenosine prevented the heat-induced-increase of DAF-16 activation and SOD-3 levels, while chronic adenosine per se induced DAF-16 activation and prevented heat-induced-increase of HSP-16.2 and SKN-1 levels. Together, these results indicate that exogenous adenosine has physiological and biochemical effects on C. elegans and describes possible purinergic signaling in worms.