bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of extracellular matrix protein fibronectin‐integrin signaling in the hippocampal dentate gyrus in epilepsy
Authors: Wu Xin , Clossen Bryan , Muthuchamy Mariappan , Reddy Doodipala 
Published: November 2023

Epilepsy affects ~3 million people in the United States alone. There is no specific drug for curing epilepsy or preventing epileptogenesis, a process whereby a normal brain becomes progressively epileptic due to precipitating factors. Integrins as membrane receptors on neurons play an important role in the development of neuroplasticity in the brain. Integrin recruitment and relocalization, and extracellular matrix (ECM) protein‐integrin attachments have been reported to dynamically change their position during cell spreading and migration. We propose that ECM protein fibronectin‐integrin interaction directly affects epileptogenesis, as well as fibronectin‐integrin bond formation and cell elasticity (remodeling) are altered in epilepsy. Here, we tested this hypothesis in adult mouse hippocampal dentate granule cells (DGCs) in the kindling model of epilepsy by direct intra‐hippocampal drug infusion and immunocytochemistry, and nanoscale atomic force microscopy (AFM). The fibronectin receptor α5β1‐integrin staining intensity in DGCs from epilepsy mice was about 22% stronger than in control. Mice were treated after kindling stage 1–2 with intra‐hippocampal injection of β1‐integrin monoclonal antibody (mAb, 100 μg/ml). The normalized electrographic after discharge threshold was 2.25‐fold higher than control group. The duration of seizure behavior and the duration of electrographic afterdischarge were inhibited by 23% and 20% after β1‐integrin application, respectively (p<0.05). In AFM study, the unbinding force (25.6 ± 0.2 pN) and binding probability between fibronectin‐coated AFM probe and membrane integrins in epilepsy DGCs were 49% and 18% lower than control, respectively (p<0.05). Moreover, the cell elasticity, partially representing changes in cytoskeletal reorganization, was 66% increased in epilepsy. Treatment with α5β1‐integrin mAb significantly reversed this membrane dysfunction. These results indicate that fibronectin‐adhesive activities directly modulate development of epilepsy, and are functional dynamic and primarily bound to α5β1 integrin. Integrin signaling pathway may offer new targets for the prevention or treatment of epilepsy.Support or Funding Information(1) 2014–2015, Special Seed grant from Dr. George C.Y. Chiou and the Institute of Ocular Pharmacology, Texas A&M Health Science Center (Xin Wu ‐ PI). (2) 2013–2018, CounterACT Program, NIH, NINDS U01 NS083460 (Doodipala Reddy ‐ PI)
Neurotensin Depresses GABA Type‐B Receptor‐Mediated Neurotransmission in the Substantia Nigra through Pre‐ and Postsynaptic Mechanisms
Authors: Tschumi Christopher W , Beckstead Michael J 
Published: November 2023

Midbrain dopamine neurons play physiological roles in many processes including reward learning and motivated behavior. Conversely, dysfunction of these neurons is implicated in disorders such as schizophrenia and drug abuse. Midbrain dopamine neurons are tonically inhibited by γ‐Aminobutyric acid (GABA)ergic inputs from multiple brain regions. Neurotensin (NT) is a neuropeptide which modulates midbrain dopamine neuron excitability through multiple mechanisms, including a decrease of GABA mediated inhibition of dopamine neurons. However, it is not known if NT acts post‐synaptically on GABA type‐B receptor signaling, pre‐synaptically at GABA terminals to alter GABA release, or through a combination of synaptic mechanisms. Here we utilize whole cell patch‐clamp electrophysiology of dopamine neurons in brain slices to show that neurotensin acts both pre‐ and post synaptically to decreases GABA type‐B receptor‐mediated currents in the substantia nigra in mice. Bath perfusion of neurotensin produced a sustained depression of GABA type‐B receptor‐mediated currents that was more pronounced when GABA was released endogenously (due to electrical stimulation) compared to when GABA was directly applied to the cell (via iontophoresis). GABA type‐B receptor mediated currents exhibited paired pulse depression when currents were elicited with electrical stimulation, but not GABA iontophoresis. Bath application of neurotensin increased the paired pulse ratio with electrical stimulation but had no effect on paired pulse currents elicited by GABA iontophoresis, providing further evidence neurotensin modulates GABA release. As NT is an endogenous peptide present at high levels in the midbrain, determining the mechanism of action by which NT alters midbrain dopamine neuron excitability is a crucial step in understanding the importance of NT in dopamine mediated behavior and related disorders.Support or Funding InformationSupport provided by NIH R01 DA 32701
CANNABINOIDS ARE NEUROPROTECTIVE AGAINST HIV‐1 TAT AND OCCLUDE THE TAT‐INDUCED DECREASE IN GABAERGIC NEUROTRANSMISSION IN PREFRONTAL CORTEX SLICES
Authors: Xu Changqing , Hermes Douglas J , Mackie Ken , Lichtman Aron H , Ignatowska‐Jankowska Bogna M , Fitting Sylvia 
Published: November 2023

In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV‐1) is now considered a chronic disease that specifically targets the brain and causes a high prevalence of mild forms of neurocognitive impairments, also referred to as HIV‐associated neurocognitive disorders (HAND). HAND is due in part to defects in synaptic neurotransmission that leads to synaptodendritic injury, including damage to synapses and dendrites. Endocannabinoids have been suggested to protect central nervous system (CNS) neurons in different disease models of toxicity, but their effect in HAND are poorly known. To address this issue primary prefrontal cortex (PFC) neuron culture studies examined the neuroprotective effects of the synthetic cannabinoid WIN55,212‐2 and the endocannabinoid N‐arachidonoyl ethanolamine (anandamide/AEA) on HIV‐1 Tat excitotoxicity and neuronal survival. Data demonstrated that WIN55,212‐2 and AEA are protective against HIV‐1 Tat‐induced increases in [Ca2+]i as well as neuron injury and cell death via a cannabinoid 1 receptor (CB1R)‐mediated mechanism. Further, whole‐cell patch‐clamp recordings were performed on PFC slices to assess cannabinoid effects on GABAergic neurotransmission in the presence of HIV‐1 Tat. Results indicated a HIV‐1 Tat concentration dependent (5 – 50 nM) decrease in the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) but not spontaneous IPSCs (sIPSCs). Zero external calcium and cadium chloride (CdCl2, 200 μM), which blocks high and low threshold voltage‐dependent calcium currents, prevented the significant Tat‐induced decrease in mIPSCs. Interestingly, bath‐applied WIN55,212‐2 or AEA that significantly decreased the frequency but not amplitude of mIPSCs and/or spontaneous IPSCs (sIPSCs) blocked a further down‐regulation of IPSCs by Tat. Lastly, pretreatment with SR141716A, a CB1R antagonist, prevented the AEA‐induced decrease in IPSCs frequency without any further Tat effect. These results suggest that Tat significantly decreases GABAergic neurotransmission at the level of an action potential‐independent release of GABA due to the influx of extracellular calcium, partially via voltage‐dependent calcium currents. Additionally, bath application of cannabinoids following or prior Tat treatment occluded the Tat‐induced decrease in GABA release, with cannabinoids acting via a CB1R‐related mechanism. Understanding the effects of cannabinoids in the context of neuro AIDS may uncover novel therapeutic targets for HAND and other diseases in which cognitive deficits occur.Support or Funding InformationNIDA R00 DA033878, T32 DA007244
Long term administration of methamphetamine in Tat mice causes altered behavior and neuroplasticity gene expression – Implications in neuroAIDS
Authors: Nookala Anantha Ram , Kumar Anil 
Published: November 2023

Methamphetamine (MA) abuse is common among individuals infected with HIV‐1 and is shown to affect the disease progression towards AIDS. These HIV‐1 infected individual's exhibit greater neuronal injury and higher cognitive decline. Several HIV‐1 proteins, specifically gp120 and HIV‐1 Tat have been shown to affect neurocognition. HIV‐1 Tat, a viral protein released early during HIV‐1 replication has been implicated in HIV‐associated neurotoxicity mediated through production of pro‐inflammatory cytokines, reactive oxygen species and dysregulation of neuroplasticity among many other factors in the central nervous system. However, combined effect of methamphetamine and HIV‐1 Tat on the alteration of locomotor function, anxiety, memory and their correlation to neuroplasticity gene expression is not well documented. The present study was undertaken to determine the combined effect of methamphetamine and HIV‐1 Tat on behavior and neuroplasticity gene expression. Doxycycline (DOX)‐inducible HIV‐1 Tat (1–86) transgenic mice were administered 6mg/kg MA twice a day. Expression of Tat in various brain regions was confirmed by RT‐PCR. Behavior studies were performed in both males and female mice after 2 weeks of MA administration. As measured by open field assay, the ambulatory activity was decreased in Tat mice. However, administration of MA increased the ambulatory activity in both Tat −ve mice and Tat +ve mice. MA administered mice have showed decreased anxiety levels as assessed by the time spent in the light compartment during Light/dark box assay. In water maze task, there was a significant increase in escape latency in all the groups compared to control mice, particularly more in Tat transgenic mice that were administered MA. We looked at the alterations in behavior with correlation to neuroplasticity gene expression. We observed a significant decrease in the protein expression of CNTF, Lif in entorhinal cortex and prefrontal cortex. Furthermore, we observed decrease in mRNA expression of CNTF, IL‐11 and BDNF in parietal cortex. This study therefore provides novel insights into the interaction of HIV‐1 Tat and MA on the dysregulated expression of various neuroplasticity genes in different brain regions.Support or Funding InformationThe work was supported by National Institute on Drug Abuse grants DA025528 & DA025011.
A multi‐herbal extract HT047 promotes long‐term functional recovery after focal cerebral ischemia in rats
Authors: Song Jungbin , Lee Donghun , Kim Young‐Sik , Kim Hyun Soo , Lee Hyun Jeong , Lee Seunggyeong , Lee Sung Hyun , Kim Hocheol 
Published: November 2023

HT047 is a multi‐herbal extract consisting of Pueraria lobata root and Scutellaria baicalensis root which have been used to treat stroke in traditional Korean medicine. Since 2000, we screened more than 200 medicinal herb extracts for neuroprotective activities in animal stroke models. Pueraria lobata root and Scutellaria baicalensis root were identified as the most potent extracts in this screen and neuroprotective activities of individual herb were further enhanced by the cotreatment. Recently, bioactive constituents of HT047 have been reported to increase the expression of trophic factors in ischemic brain such as vascular endothelial growth factor (VEGF) and brain‐derived neurotrophic factor (BDNF) that are crucial for enhancing neurorestoration, leading to functional recovery after stroke. In the present study, we investigated the effects of delayed HT047 treatment on long‐term motor recovery after cerebral ischemia in rats. Sprague‐Dawley rats were subjected to 60 min of middle cerebral artery occlusion (MCAO). HT047 was orally administered to rats for consecutive 14 days at a dose of 300 mg/kg starting 24 h after MCAO and then rats were received chow diet containing 1.35 % HT047 up to 6 months. Long‐term functional outcomes were assessed by the rotarod test and the forelimb placing test during subacute (weekly intervals for one month) and recovery (monthly intervals up to 6 months) phases. HT047 accelerated recovery of rotarod performance during a subacute period and protected age‐related decline during a chronic recovery phase. The forelimb placing scores of HT047 group were significantly higher than those of control group during the whole testing period. These findings indicate that delayed HT047 treatment initiated at 24 h after stroke accelerates the recovery of motor function followed by sustained enhancement during a recovery phase. The enhancement of neurorestorative events including angiogenesis, dendritic branching, synaptogenesis, and axonal sprouting may contribute to the therapeutic benefits of HT047 in the treatment of stroke.Support or Funding InformationThis study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI15C0051).
The α2 Adrenergic Receptor as a Novel Target for Alzheimer's Disease
Authors: Gannon Mary , Peng Yin , Jiao Kai , Wang Qin 
Published: November 2023

Alzheimer's disease (AD) is the most common form of dementia, and is the only cause of death within the top 10 in America that cannot be prevented, cured, or slowed. Alterations of the noradrenergic (NA) system occur early in AD. However, the relevance of NA dysfuntion to AD pathogenesis and the therapeutic potential of NA components for AD are unknown. We have previously shown that activation of the α2 adrenergic receptor (α2AR) increases amyloidogenic processing of amyloid precursor protein (APP), and therefore amyloid β (Aβ) load in the brain. In this study, we sought to investigate α2AR expression and activity with AD advancement, and test whether a blockade of the α2AR slows AD progression using an AD transgenic mouse model. We examined α2AR coupling to G‐protein by use of a [35S]GTPγS radioligand binding assay in both 5 week and 7.5 month old APP/PS1 mice and their nontransgenic littermates. At the earlier time point, prior to AD pathology, no difference was found between APP/PS1 and nontransgenic mice. However, at 7.5 months, after AD pathology is profound, increased α2AR‐G protein coupling efficiency was observed in APP/PS1 mice, suggesting that α2AR function is enhanced as AD progresses. Furthermore, we treated 8 month‐old APP/PS1 mice with an α2AR antagonist, idazoxan, for 8 weeks and evaluated their neuropathology and cognitive behaviors. Compared to saline treatment, treatment with idazoxan reduced Aβ load in both the hippocampus and cortex, and, more importantly, improved cognitive performance of APP/PS1 mice on the Morris water maze. In conclusion, our studies suggest that α2AR activity is upregulated in APP/PS1 mice with pathological progression and that a clinical α2AAR antagonist is effective in decreasing Aβ plaque load and improving cognition, even when started after the accumulation of Aβ plaques. Therefore, targeting the α2AR represents a promising therapeutic strategy for AD.Support or Funding InformationThis study is supported by NIH Grant AG042716 (to Q.W.).
Investigation of Dithiolethione 59 as Potential Neuroprotective Antiparkinsonian Agent
Authors: Betharia Swati , Brown Dennis , Fuentes Steven , Aoude Iman 
Published: November 2023

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by the disintegration of nigrostriatal dopaminergic neurons. The resulting loss of dopamine gives rise to the cardinal symptoms of the disease, including resting tremor, rigidity, and bradykinesia. Oxidative stress and depletion of the ubiquitous antioxidant glutathione (GSH) have been implicated in the pathophysiology of PD. Towards the development of novel neuroprotective antiparkinsonian agents, we report the pharmacological characterization of the sulfur‐containing dithiolethone (DTT) 59 in the dopaminergic neuroblastoma SH‐SY5Y cell line. DTTs are known activators of the transcription factor nuclear factor erythroid‐2 factor (Nrf2). Activation of Nrf2 is associated with the induction of various cytoprotective antioxidants such as GSH, the catalytic unit of enzyme glutamate cysteine ligase (GCLC), the cytosolic isoform of glutathione S‐transferase (GSTP1), the light chain subunit of the cysteine‐glutamate transporter (xCT), and the phase II enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1). Compound 59 was found to dose‐dependently increase cellular levels of total GSH. 59 also provided significant neuroprotection in the 6‐hydroxydopamine (6‐OHDA) model of neurotoxicity at concentrations as low as 10 μM. Mechanistic studies showed a concentration‐ and time‐dependent increase in NQO1 at both the message and protein levels; however, GCLC, GSTP1 and xCT levels remained unchanged. Pretreatment of SH‐SY5Y cells with the GCLC inhibitor buthionine sulfoximine (BSO) was found to block 59‐mediated GSH induction. BSO treatment also abolished the protective properties of 59, indicating that GSH induction is important for neuroprotection. While the Nrf2 pathway did not appear to be involved in this induction, these data suggest that 59 is a potential neuroprotective antiparkinsonian agent and warrants additional exploration.Support or Funding InformationThis research was supported by Manchester University College of Pharmacy, Natural and Health Sciences.
EFFECTS OF UCH‐L1 INHIBITION IN IMMORTALIZED DOPAMINERGIC NEURONS
Authors: Winner Brittany Michele , Zhang Harue , Goudreau John , Lookingland Keith 
Published: November 2023

In Parkinson disease (PD), a debilitating neurodegenerative disorder characterized by a host of motor and non‐motor symptoms, neurons in the substantia nigra pars compacta (SN) progressively degenerate. The effect of this degeneration is the loss of striatal dopamine (DA), which famously results in bradykinesia, postural instability, shuffling gait, and resting tremor. Animal and cellular models only partially recapitulate the progression of the disease, since much is still not known about the etiology of PD. Using cell lines affords a method in which to manipulate parameters in a homogeneous population whereby we can study phenomena occurring specifically in dopaminergic neurons. The dopaminergic cell line, MN9D, was generated by fusing mouse neuroblastoma cells with primary mouse mesencephalon neurons. A key feature of these cells is their ability to be differentiated using sodium butyrate in the culture medium, which halts their cell cycle and makes them look morphologically like neurons. Expression of the dopamine transporter and tyrosine hydroxylase, markers of dopamine neurons, are also highly expressed after differentiation of MN9D cells. In these cells, we have studied components of the ubiquitin proteasome system (UPS) such as parkin and UCH‐L1, which are two genes found mutated in familial PD. The latter, UCH‐L1 (ubiquitin carboxy‐terminal hydrolase L1), is a neuron‐specific, highly expressed de‐ubiquitinating enzyme thought to play a role in the susceptibility of mouse SN neurons exposed to the toxicant MPTP (active metabolite is MPP+). UCH‐L1 acts to remove monomeric ubiquitin from protein substrates, regulating proteasome activity and replenishing the pool of monomeric ubiquitin to be tagged on to new substrates. In MN9D cells with MPP+ treatment, we have found that intracellular dopamine, intracellular DOPAC, and UCH‐L1 protein all decrease. In addition, when we treated cells with LDN‐57444 (a UCH‐L1 inhibitor), DA but not DOPAC decreased in these cells, highlighting a possible link between the loss of DA and loss of function of UCH‐L1. These studies will help shed light on the dynamics between UPS function and dopamine synthesis and turnover in MN9D cells as an in vitro model for isolated SN neurons.Support or Funding InformationT32 Pre‐Doctoral Training Grant Institute for Integrative Toxicology; PIs Grant: 1R01 NS065338‐01A2
Loss of GPR37 Increases Susceptibility to Demyelination
Authors: Coleman Brilee M. , Li Fengqiao , Giddens Michelle M. , Hall Randy A. 
Published: November 2023

GPR37 is an orphan G protein‐coupled receptor that is highly expressed in the brain. Previous work has shown that GPR37 is a receptor for the secreted neuroprotective and glioprotective factor prosaposin and that prosaposin acts through GPR37 to protect cultured astrocytes from oxidative stress‐induced cell death (Meyer et al., Proc. Natl. Acad. USA, 2013). Furthermore, it has previously been shown that prosaposin enhances the survival of oligodendroglia in vitro and also promotes myelination in vivo (Hiraiwa et al., Proc. Natl. Acad. Sci. USA, 1997; Hiraiwa et al., Glia, 1999). Interestingly, several reports indicate that GPR37 is expressed at particularly high levels in oligodendrocytes (Imai et al., Cell, 2001; Cahoy et al., J. Neurosci., 2008). However, despite the aforementioned evidence for GPR37 expression in oligodendroglia, the role(s) that GPR37 may play in oligodendroglial biology remain uncharacterized. Here we show that GPR37‐knockout (GPR37‐KO) mice display more rapid and extensive demyelination than their wild type (WT) counterparts in the cuprizone model of demyelination. Furthermore, we observed that GPR37‐KO mice do not show an increased loss of oligodendrocyte precursor cells or mature oligodendrocytes. Parallel studies on primary cultures of oligodendrocytes also revealed a protective role for GPR37. From these data, we conclude that loss of GPR37 alters oligodendrocyte physiology and increases susceptibility to demyelination, independent of effects on oligodendrocyte proliferation or differentiation. The present work identifies GPR37 as a potential drug target for the treatment of demyelinating diseases such as multiple sclerosis. Ongoing studies in this area seek to elucidate the signaling pathways downstream of GPR37 that regulate oligodendrocyte physiology and support myelination.Support or Funding InformationThis research was supported through the Fast Forward program of the National Multiple Sclerosis Society.
Stalk‐dependent and Stalk‐independent Activity of the Adhesion GPCR GPR56/ADGRG1
Authors: Kishore Ayush , Hall Randy A. 
Published: November 2023

The adhesion G protein‐coupled receptors (aGPCRs) comprise an enigmatic family of 33 receptors in humans. A hallmark of the aGPCRs is the presence of a large extracellular N‐terminal (NT) domain that has been shown to inhibit receptor activity. Yet another defining characteristic of virtually all aGPCRs is the presence of a GPCR Autoproteolysis Inducing (GAIN) domain, which is found on the membrane‐proximal end of the NT and controls the autocatalytic proteolysis of the receptor into an NT protomer and seven‐transmembrane (7TM) protomer, which can stay non‐covalently associated for some time. Recently, great progress has been made to shed light upon a more detailed view of how exactly the NT regions inhibit aGPCR‐mediated signaling. Notably, two separate groups have espoused a “cryptic agonist” model of aGPCR activation wherein GAIN domain cleavage unveils a new NT stalk which serves as the receptor's agonist. In this model, the stalk is a requisite agonist for aGPCR activity and deletion of the stalk result in a signaling‐incompetent receptor. In the work presented here, we show that the stalk of the aGPCR GPR56/ADGRG1 (“G1”) is indeed necessary for activation of the certain downstream readouts (such as activation of SRF luciferase) but dispensable for others (such as the shedding of membrane‐bound TGFalpha and activation of NFAT luciferase). Moreover, a stalkless version of G1 also displays comparable activity to the highly‐active, GAIN‐cleavage‐mimetic form of G1 (G1‐deltaNT) in several measures of activity including beta‐arrestin recruitment, receptor ubiquitination, and association with Galpha13. These lines of evidence suggest that G1 is capable of both stalk‐dependent and stalk‐independent modes of signaling. Based upon our results, we propose a more nuanced model of aGPCR activation in which the NT inhibits activity of the 7TM region in two distinct ways: i) antagonizing stalk‐dependent signaling by masking the cryptic stalk peptide, and ii) directly antagonizing the inherent stalk‐independent activity of the 7TM protomer.Support or Funding InformationThis work was supported by NIH R01 award R01‐NS072394.