Neuromolecular Medicine

The medial prefrontal cortex (mPFC) is critical for both the sensory and emotional/cognitive components of pain. However, the underlying mechanism remains largely unknown. Here, we examined changes in the transcriptomic profiles in the mPFC of mice with chronic pain using RNA sequencing (RNA-seq) technology. A mouse model of peripheral neuropathic pain was established via chronic constriction injury (CCI) of the sciatic nerve. CCI mice developed sustained mechanical allodynia and thermal hyperalgesia, as well as cognitive impairment four weeks after surgery...

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model is one of the most common animal models for Parkinson's disease (PD). It is classified into three types: acute, subacute, and chronic intoxication models. The subacute model has attracted much attention for its short period and similarity to PD. However, whether subacute MPTP intoxication in mouse mimics the movement and cognitive disorders of PD still remains highly controversial. Therefore, the present study reassessed the behavioral performances of subacute MPTP intoxication in mice using open field, rotarod, Y maze,  and gait analysis at different time points (1, 7, 14, and 21 days) after modeling...

Interleukin-17A plays a crucial role in multiple sclerosis and other autoimmune diseases. Although the link between IL-17 and disease activity has been clearly demonstrated, the precise function of this cytokine remains elusive. Here, we investigated the function of astrocyte-targeted IL-17A production in GF/IL-17 transgenic mice during EAE. In particular, IL-17A is important during disease induction. In mice with transgenic IL-17A production, disease occurs earlier and peak disease is more severe, whereas remission is unimpaired...

Stroke is a leading cause of death, with a continuously increasing incidence. As a metabolic process that catabolizes glucose pyruvate and provides adenosine triphosphate (ATP), glycolysis plays a crucial role in different diseases. Phosphoglycerate kinase 1 (PGK1) facilitates energy production with biosynthesis in many diseases, including stroke. However, the exact role of PGK1/glycolysis in stroke remains to be elucidated. A rat model of middle cerebral artery occlusion (MCAO) was used to mimic ischemia/reperfusion injuries...

Anxiety is reportedly one of the most common mental changes after traumatic brain injury (TBI). Perineuronal nets (PNNs) produced by astrocytes in the lateral hypothalamus (LHA) that surround gamma-aminobutyric acid-ergic (GABAergic) neurons have been associated with anxiety. The potent anti-tumor effects of Spautin-1, a novel autophagy inhibitor, have been documented in malignant melanoma; moreover, the inhibition of autophagy is reported to mitigate anxiety disorders. However, little is known about the ability of spautin-1 to alleviate anxiety...

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration...

Transient receptor potential mucolipin-1 (TRPML1) is the most abundantly and widely expressed channel protein in the TRP family. While numerous studies have been conducted involving many aspects of TRPML1, such as its role in cell biology, oncology, and neurodegenerative diseases, there are limited reports about what role it plays in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Here we examined the function of TRPML1 in ICH-induced SBI. The caudal arterial blood of rats was injected into the caudate nucleus of basal ganglia to establish an experimental ICH model...

Rapid eye movement (REM) sleep behavior disorder (RBD) is a powerful early sign of Parkinson's disease (PD), but the pathogenetic mechanism involved in RBD remains largely unexplored. α-Synuclein has been verified to form Lewy bodies in the orexin neurons, whose activity and function rely on the orexin 1 receptor (OX1R). Dysfunction of the OX1R may induce the occurrence of RBD. Here, we determined the role of the interaction between α-Synuclein and OX1R in the pathogenesis of RBD, in vitro and in vivo...

Sleep deprivation causes significant memory impairment in healthy adults. Extensive research has focused on identifying the biological mechanisms underlying memory impairment. Microglia-mediated synaptic elimination plays an indispensable role in sleep deprivation. Here, the potential role of the CD33/TREM2 signaling pathway in modulating memory decline during chronic sleep restriction (CSR) was evaluated. In this study, adult male C57BL/6 mice were sleep-restricted using an automated sleep deprivation apparatus for 20 h per day for 7 days...

Repeated mild traumatic brain injury (rmTBI) poses adversity in the form of neurological deficits. The ignition of long-term neurological aberrations post-TBI is appended with the microbiota gut-brain axis perturbation. Herein, we examined whether quercetin, which is anti-inflammatory and antioxidant flavonoid, serves as a prebiotic and modifies the compromised microbiome gut-brain axis in rmTBI mouse model. Male C57BL/6 mice were subjected to rmTBI for 7 times. The quercetin (50 mg/kg) was administered peroral from the day1 of first injury till 7 days post-injury...

Post-stroke secondary brain damage is significantly influenced by the induction and accumulation of α-Synuclein (α-Syn). α-Syn-positive inclusions are often present in tauopathies and elevated tau levels and phosphorylation promotes neurodegeneration. Glycogen synthase kinase 3β (GSK-3β) is a known promoter of tau phosphorylation. We currently evaluated the interaction of α-Syn with GSK-3β and tau in post-ischemic mouse brain. Transient focal ischemia led to increased cerebral protein-protein interaction of α-Syn with both GSK-3β and tau and elevated tau phosphorylation...

Lithium is a mood stabilizer broadly used to prevent and treat symptoms of mania and depression in people with bipolar disorder (BD). Little is known, however, about its mode of action. Here, we analyzed the impact of lithium on synaptic vesicle (SV) cycling at presynaptic terminals releasing glutamate, a neurotransmitter previously implicated in BD and other neuropsychiatric conditions. We used the pHluorin-based synaptic tracer vGpH and a fully automated image processing pipeline to quantify the effect of lithium on both SV exocytosis and endocytosis in hippocampal neurons...

Neuroinflammation and microglial activation are involved in the pathogenesis of sepsis-associated encephalopathy (SAE). Mitochondrial dynamics emerged as a new player in the regulation of immunological processes. In this study, we aimed at exploring the effects of mitochondrial-targeted antioxidant peptide SS-31 on cognitive function in mice with SAE. In mice, SS-31 was intraperitoneally administered for seven consecutive days after cecal ligation and puncture surgery. SS-31 improved cognitive performance and survival rate of mice and alleviated hippocampal inflammation, reactive oxygen species production, and excessive mitochondrial fission...

Cerebral ischemia is the primary basis of stroke, both sharing common pathogenic origins leading to irreversible brain damage if blood supply is not restored promptly. Existing evidence indicates that carbonic anhydrase (CA) inhibitors (CAIs) may impart therapeutic benefits against ischemia-reperfusion (I/R) pathology via the adenylyl cyclase-cyclic adenosine monophosphate (cAMP) pathway. We hypothesize that CAI and cAMP activation may enhance the therapeutic outcome against I/R conditions. In this investigation, the potential of dichlorphenamide (CAI) and the role of cAMP against ischemia-reperfusion injury were evaluated using a transient global cerebral I/R (tGCI/R) model...

Ergothioneine (ET) is a naturally occurring antioxidant and cytoprotective agent that is synthesized by fungi and certain bacteria. Recent studies have shown a beneficial effect of ET on neurological functions, including cognition and animal models of depression. The aim of this study is to elucidate a possible effect of ET in rodent models of stroke. Post-ischemic intracerebroventricular (i.c.v.) infusion of ET significantly reduced brain infarct volume by as early as 1 day after infusion in rats, as shown by triphenyltetrazolium chloride (TTC) assay...

The attribution of seizure freedom is yet to be achieved for patients suffering from refractory epilepsy, e.g. Dravet Syndrome (DS). The confined ability of mono-chemical entity-based antiseizure drugs (ASDs) to act directly at genomic level is one of the factors, combined with undetermined seizure triggers lead to recurrent seizure (RS) in DS, abominably affecting the sub-genomic architecture of neural cells. Thus, the RS and ASD appear to be responsible for the spectrum of exorbitant clinical pathology. The RS distresses the 5-HT-serotonin pathway, hypomethylates genes of CNS, and modulates the microRNA (miRNA)/long non-coding RNA (lncRNA), eventually leading to frozen molecular alterations...

The wingless-related integration site (Wnt) signaling pathway plays an essential role in embryonic development and nervous system regulation. It is critically involved in multiple types of neuropathic pain (NP), such as HIV-related NP, cancer pain, diabetic neuralgia, multiple sclerosis-related NP, endometriosis pain, and other painful diseases. Wnt signaling is also implicated in the pain induced by sciatic nerve compression injury and selective spinal nerve ligation. Thus, the Wnt signaling pathway may be a potential therapeutic target for NP...

Molecules that selectively act on N-methyl-D-aspartate (NMDA) receptors may have a multidirectional effect by modulating the activity of NMDARs, affecting their active sites as well as by changing the composition of their subunits. The results of the clinical trials conducted so far in mood disorders and schizophrenia indicate that such agents may become new effective drugs for the treatment of these diseases. Number of spider neurotoxins e.g. ctenitoxins extracted from Phoneutria sp. venom act as potent and selective NMDAR blockers that do not disturb cortical and hippocampal glutamate signaling, LTP generation and synaptic neurochemistry...

Quercetin is a polyphenolic bioactive compound highly enriched in dietary fruits, vegetables, nuts, and berries. Quercetin and its derivatives like rutin and hyperoside are known for their beneficial effects in various neurological conditions including epilepsy. The clinical studies of quercetin and its derivatives in relation to epilepsy are limited. This review provides the evidence of most recent knowledge of anticonvulsant properties of quercetin and its derivatives on preclinical studies. Additionally, the studies demonstrating antiseizure potential of various plants extracts enriched with quercetin and its derivatives has been included in this review...

Intercellular adhesion molecule 1 (ICAM1) is a vessel adhesion protein induced during brain vascular inflammation, which could be closely linked with the development of Alzheimer's disease (AD). This study investigated the effect of ICAM1 on amyloid-degrading enzymes (ADEs) in endothelial cells and their potential involvement in inflammation and AD progression. TNF-α treatment increased ICAM1 in human brain microvascular endothelial cells (HBMVECs) but decreased the neprilysin (NEP) protein level. Knock-down of ICAM1 using siRNA enhanced NEP, which increased the degradation of amyloid-β...