Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.

Disrupted copper availability in the central nervous system (CNS) is implicated as a significant feature of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Solute carrier family 31 member 1 (Slc31a1; Ctr1) governs copper uptake in mammalian cells and mutations affecting Slc31a1 are associated with severe neurological abnormalities. Here, we examined the impact of decreased CNS copper caused by ubiquitous heterozygosity for functional Slc31a1 on spinal cord motor neurons in Slc31a1+/- mice.

High-throughput surface epitope immunoaffinity isolation of extracellular vesicles and downstream analysis.

Extracellular vesicles (EVs), including exosomes, have significant potential for diagnostic and therapeutic applications. The lack of standardized methods for efficient and high-throughput isolation and analysis of EVs, however, has limited their widespread use in clinical practice. Surface epitope immunoaffinity (SEI) isolation utilizes affinity ligands, including antibodies, aptamers, or lectins, that target specific surface proteins present on EVs.

Involvement of relaxin-family peptide-3 receptor (RXFP3) in the ventral dentate gyrus of the hippocampus in spatial and fear memory in rats.

The neuropeptide relaxin-3 and its cognate receptor, relaxin family peptide-3 receptors (RXFP3), have been implicated in modulating learning and memory processes, but their specific roles remain unclear. This study utilized behavioral and molecular approaches to investigate the effects of putatively reversible blockade of RXFP3 in the ventral dentate gyrus (vDG) of the hippocampus on spatial and fear memory formation in rats. Male Wistar rats received bilateral vDG cannula implantation and injections of the RXFP3 antagonist, R3(BΔ23-27)R/I5 (400 ng/0.

Microglial ferroptotic stress causes non-cell autonomous neuronal death.

Background: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.

Transdermal Application of Soluble Cu(atsm) Increases Brain and Spinal Cord Uptake Compared to Gavage with an Insoluble Suspension.

Cu(atsm) is a blood-brain barrier permeant copper(II) compound that is under investigation in human clinical trials for the treatment of neurodegenerative diseases of the central nervous system (CNS). Imaging in humans by positron emission tomography shows the compound accumulates in affected regions of the CNS in patients. Most therapeutic studies to date have utilised oral administration of Cu(atsm) in an insoluble form, as either solid tablets or a liquid suspension.

CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 mice with a C57BL/6 background.

The synthetic copper-containing compound, CuATSM, has emerged as one of the most promising drug candidates developed for the treatment of amyotrophic lateral sclerosis (ALS). Multiple studies have reported CuATSM treatment provides therapeutic efficacy in various mouse models of ALS without any observable adverse effects. Moreover, recent results from an open label clinical study suggested that daily oral dosing with CuATSM slows disease progression in patients with both sporadic and familial ALS, providing encouraging support for CuATSM in the treatment of ALS.

Copper-ATSM as a Treatment for ALS: Support from Mutant SOD1 Models and Beyond.

The blood-brain barrier permeant, copper-containing compound, Cu(atsm), has successfully progressed from fundamental research outcomes in the laboratory through to phase 2/3 clinical assessment in patients with the highly aggressive and fatal neurodegenerative condition of amyotrophic lateral sclerosis (ALS). The most compelling outcomes to date to indicate potential for disease-modification have come from pre-clinical studies utilising mouse models that involve transgenic expression of mutated superoxide dismutase 1 (SOD1). Mutant SOD1 mice provide a very robust mammalian model of ALS with high validity, but mutations in SOD1 account for only a small percentage of ALS cases in the clinic, with the preponderant amount of cases being sporadic and of unknown aetiology.

Should we change our approach to resuscitating victims of femoral fracture? A clinical experience in a busy trauma hospital in Shiraz, Iran.

Purpose: Traumatic hemorrhagic shock is a life-threatening event worldwide. Severe brain trauma accompanying femoral fractures can trigger inflammatory responses in the body and increase pre-inflammatory cytokines such as TNF-α, IL-1. The primary treatment in these cases is hydration with crystalloids, which has both benefits and complications.

Treating Alzheimer's disease by targeting iron.

No disease modifying drugs have been approved for Alzheimer's disease despite recent major investments by industry and governments throughout the world. The burden of Alzheimer's disease is becoming increasingly unsustainable, and given the last decade of clinical trial failures, a renewed understanding of the disease mechanism is called for, and trialling of new therapeutic approaches to slow disease progression is warranted. Here, we review the evidence and rational for targeting brain iron in Alzheimer's disease.

Protective effects of ex-527 on cerebral ischemia-reperfusion injury through necroptosis signaling pathway attenuation.

Necroptosis, a novel type of programmed cell death, is involved in ischemia-reperfusion-induced brain injury. Sirtuin 1 (Sirt1), as a well-known member of histone deacetylase class III, plays pivotal roles in inflammation, metabolism, and neuron loss in cerebral ischemia. We explored the relationship between Sirt1 and the necroptosis signaling pathway and its downstream events by administration of ex-527, as a selective and potent inhibitor of Sirt1, and necrostatin-1 (nec-1), as a necroptosis inhibitor, in an animal model of focal cerebral ischemia.

Coenzyme Q10 supplementation improves acute outcomes of stroke in rats pretreated with atorvastatin.

Objectives: Coenzyme Q10 (CoQ10, ubiquinone) stands among the safest supplements in the elderly to protect against cardiovascular disorders. Noteworthy, CoQ10 deficiency is common in many surviving stroke patients as they are mostly prescribed statins for the secondary prevention of stroke incidence lifelong. Accordingly, the current study aims to experimentally examine whether CoQ10 supplementation in animals receiving atorvastatin may affect acute stroke-induced injury.

Necroptosis Resumes Apoptosis in Hippocampus but Not in Frontal Cortex.

Cell death subsequent to or concurrent with neuroinflammation results in some damages like neuron loss and spatial memory impairment. In this study, we demonstrated the temporal pattern of neuroinflammation, necroptotic, and apoptotic cell deaths in hippocampus and frontal cortex following intracerebroventricular administration of lipopolysaccharide (LPS). We evaluated receptor interacting protein kinase 1 (RIP1), RIP3, and two related metabolic enzymes including glutamate-ammonia ligase (GLUL) and glutamate dehydrogenase (GLUD) as necroptosis factors.

Inactivation of nucleus incertus impairs passive avoidance learning and long term potentiation of the population spike in the perforant path-dentate gyrus evoked field potentials in rats.

Involvement of brainstem nucleus incertus (NI) in hippocampal theta rhythm suggests that this structure might play a role in hippocampal-dependent learning and memory. In the present study we aimed to address if NI is involved in an avoidance learning task as well as dentate gyrus (DG) short-term and long-term potentiation. Lidocaine was injected into the NI to transiently inactivate the nucleus, and control rats received saline.

Cannabidiol Post-Treatment Alleviates Rat Epileptic-Related Behaviors and Activates Hippocampal Cell Autophagy Pathway Along with Antioxidant Defense in Chronic Phase of Pilocarpine-Induced Seizure.

Abnormal and sometimes severe behavioral and molecular symptoms are usually observed in epileptic humans and animals. To address this issue, we examined the behavioral and molecular aspects of seizure evoked by pilocarpine. Autophagy can promote both cell survival and death, but there are controversial reports about the neuroprotective or neurodegenerative effects of autophagy in seizure.

RIP1 Inhibition Rescues from LPS-Induced RIP3-Mediated Programmed Cell Death, Distributed Energy Metabolism and Spatial Memory Impairment.

Receptor interacting protein 1 (RIP1) has a critical role in initiation of programmed necrosis or necroptosis. RIP1 in a close collaboration with RIP3 not only mediates necroptosis but also is involved in apoptosis and inflammatory signaling. However, the interpretation of the distinct function of RIP1 and RIP3 is complicated.

Nucleus incertus inactivation impairs spatial learning and memory in rats.

Nucleus incertus (NI) is a pontine nucleus which releases mainly GABA and relaxin-3 in rats. Its suggested functions include response to stress, arousal, and modulation of hippocampal theta rhythm. Since the role of NI in learning and memory has not been well characterized, therefore the involvement of this nucleus in spatial learning and memory and the aftermath hippocampal levels of c-fos and pCREB were evaluated.

Acute administration of Zn, Mg, and thiamine improves postpartum depression conditions in mice.

Background: Postpartum depression (PPD) affects approximately half of new mothers. Chronic exposure to progesterone during pregnancy and its withdrawal following delivery increases depression and anxiety. In addition, there are complex interactions between hormones, neurotransmitters, and trace elements.

Postpartum depression and role of serum trace elements.

Postpartum depression (PPD) is a major depressive disorder that most often emerges within 6 to 12 weeks of delivery, but can happen any time up to 1 year after birth. In developed countries, the incidence of postnatal depression is about 10-15% in adult women depending upon the diagnostic criteria, timing of screening and screening instruments used. Mothers with depressive symptoms have been found to have more complex behavioral contacts with their children; this situation can damage family relationships, and even leads to infanticide.