Iron Deposition and Ferroptosis in the Spleen in a Murine Model of Acute Radiation Syndrome.

Total body irradiation (TBI) can result in death associated with hematopoietic insufficiency. Although radiation causes apoptosis of white blood cells, red blood cells (RBC) undergo hemolysis due to hemoglobin denaturation. RBC lysis post-irradiation results in the release of iron into the plasma, producing a secondary toxic event.

Involvement of Lateral Habenula Dysfunction in Repetitive Mild Traumatic Brain Injury-Induced Motivational Deficits.

Affective disorders including depression (characterized by reduced motivation, social withdrawal, and anhedonia), anxiety, and irritability are frequently reported as long-term consequences of mild traumatic brain injury (mTBI) in addition to cognitive deficits, suggesting a possible dysregulation within mood/motivational neural circuits. One of the important brain regions that control motivation and mood is the lateral habenula (LHb), whose hyperactivity is associated with depression. Here, we used a repetitive closed-head injury mTBI model that is associated with social deficits in adult male mice and explored the possible long-term alterations in LHb activity and motivated behavior 10-18 days post-injury.

Transcriptomic Analysis of Mouse Brain After Traumatic Brain Injury Reveals That the Angiotensin Receptor Blocker Candesartan Acts Through Novel Pathways.

Traumatic brain injury (TBI) results in complex pathological reactions, where the initial lesion is followed by secondary inflammation and edema. Our laboratory and others have reported that angiotensin receptor blockers (ARBs) have efficacy in improving recovery from traumatic brain injury in mice. Treatment of mice with a subhypotensive dose of the ARB candesartan results in improved functional recovery, and reduced pathology (lesion volume, inflammation and gliosis).

Comparison of the effects of osmotic pump implantation with subcutaneous injection for administration of drugs after total body irradiation in mice.

The increasing potential for radiation exposure from nuclear accidents or terrorist activities has intensified the need to develop pharmacologic countermeasures against injury from total body irradiation (TBI). Many initial experiments to develop and test these countermeasures utilize murine irradiation models. Yet, the route of drug administration can alter the response to irradiation injury.

Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib.

Purpose: Prevalence of non-AIDS-defining cancers (NADCs) has increased in the era of potent antiretroviral treatments. Incidence rates of NADCs now exceed AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by interactions between antiretrovirals and chemotherapy mostly via inhibition or induction of CYP3A4.

Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling.

Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e.

Dopamine promotes striatal neuronal apoptotic death via ERK signaling cascades.

Although the mechanisms underlying striatal neurodegeneration are poorly understood, we have shown that striatal pathogenesis may be initiated by high synaptic levels of extracellular dopamine (DA). Here we investigated in rat striatal primary neurons the mobilization of the mitogen-activated protein kinase (MAPK) signaling pathways after treatment with DA. Instead of observing an elevation of the archetypical pro-cytotoxic MAPKs, p-JNK and p-p38 MAPK, we found that DA, acting through D1 DA receptors, induced a sustained stimulation of the phosphorylated form of extracellular signal-regulated kinase (p-ERK) via a cAMP/protein kinase A (PKA)/Rap1/B-Raf / MAPK/ERK kinase (MEK) pathway.

Alterations of striatal glutamate transmission in rotenone-treated mice: MRI/MRS in vivo studies.

Animal models treated with agricultural chemicals, such as rotenone, reproduce several degenerative features of human central nervous system (CNS) diseases. Glutamate is the most abundant excitatory amino acid transmitter in the mammalian central nervous system and its transmission is implicated in a variety of brain functions including mental behavior and memory. Dysfunction of glutamate neurotransmission in the CNS has been associated with a number of human neurodegenerative diseases, either as a primary or as a secondary factor in the excitotoxic events leading to neuronal death.

Depolarization and neurotransmitter regulation of vasopressin gene expression in the rat suprachiasmatic nucleus in vitro.

Vasopressin (VP) transcription in the rat suprachiasmatic nucleus (SCN) in organotypic culture was studied by in situ hybridization histochemistry using an intron-specific VP heteronuclear RNA probe. The circadian peak of VP gene transcription in the SCN in vitro is completely blocked by a 2 h exposure to tetrodotoxin (TTX) in the culture medium, and this TTX inhibition of VP gene transcription is reversed by exposure of the SCN to either forskolin or potassium depolarization. This suggests that an intrinsic, spontaneously active neuronal mechanism in the SCN is responsible for the cAMP- and depolarization-dependent pathways involved in maintaining peak VP gene transcription.

Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism.

Many neurodegenerative diseases associated with functional Tau dysregulation, including Alzheimer's disease (AD) and other tauopathies, also show alpha-synuclein (alpha-Syn) pathology, a protein associated with Parkinson's disease (PD) pathology. Here we show that treatment of primary mesencephalic neurons (48 h) or subchronic treatment of wild-type (WT) mice with the Parkinsonism-inducing neurotoxin MPP+/MPTP, results in selective dose-dependent hyperphosphorylation of Tau at Ser396/404 (PHF-1-reactive Tau, p-Tau), with no changes in pSer202 but with nonspecific increases in pSer262 levels. The presence of alpha-Syn was absolutely mandatory to observe MPP+/MPTP-induced increases in p-Tau levels, since no alterations in p-Tau were seen in transfected cells not expressing alpha-Syn or in alpha-Syn-/- mice.

Highly potent and specific GSK-3beta inhibitors that block tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson's disease.

Research by Klein and co-workers suggests that the inhibition of GSK-3beta by small molecules may offer an important strategy in the treatment of a number of central nervous system (CNS) disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorders. Based on results from kinase-screening assays that identified a staurosporine analogue as a modest inhibitor of GSK-3beta, a series of 3-indolyl-4-indazolylmaleimides was prepared for study in both enzymatic and cell-based assays. Most strikingly, whereas we identified ligands having poor to high potency for GSK-3beta inhibition, only ligands with a Ki value of less than 8 nM, namely maleimides 18 and 22, were found to inhibit Tau phosphorylation at a GSK-3beta-specific site (Ser 396/404).

Modulation of the trafficking of the human serotonin transporter by human alpha-synuclein.

alpha-Synuclein (alpha-Syn), a protein primarily localized in the presynaptic compartment of neurons, is known to regulate dopaminergic neurotransmission by negatively modulating dopamine transporter activity and regulating its trafficking to or away from the cell surface. Given the considerable homology between dopamine transporters and the serotonin (5-HT) transporter (SERT), we examined whether alpha-Syn could similarly regulate SERT function. Increasing expression levels of human alpha-Syn gradually decreased [(3)H]5-HT uptake by human SERT in cotransfected Ltk(-) cells, by diminishing its V(max) without changing its K(m), as compared to cells expressing only SERT.

Bcl-xL and caspase inhibition increase the survival of rat oxytocin and vasopressin magnocellular neurons in organotypic culture.

Hypothalamic magnocellular neurons (MCNs) are highly vulnerable to axotomy-induced cell death in vivo and in vitro. In this study, we determined whether the anti-apoptotic agent Bcl-xL, a member of the Bcl-2 family which prevents programmed cell death in the central nervous system, can rescue oxytocin (OT) and vasopressin (VP) MCNs in the supraoptic nucleus (SON) in organotypic culture. We found that the novel, membrane permeant form of Bcl-xL that we employed in these studies protected both OT and VP MCNs from degeneration as long as the Bcl-xL was present in the medium.

Differential effects of forskolin on tyrosine hydroxylase gene transcription in identified brainstem catecholaminergic neuronal subtypes in organotypic culture.

The regulation of gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, was studied in brainstem noradrenergic nuclei, locus coeruleus (LC), A2 and A1, in vitro. Several novel experimental approaches employed in this study included: (i) the development of a slice-explant model in which these brainstem nuclei maintained a high survival of the noradrenergic neurons, an organotypic topology and the coexpression of two identifying markers in addition to TH, i.e.

Abnormal migration of human wild-type alpha-synuclein upon gel electrophoresis.

Alpha-synuclein aggregates have been linked to the pathogenesis of Parkinson's disease (PD), with Lewy bodies (LBs) and Lewy neurites (LNs) constituting the pathological hallmarks in the brains of patients with PD and dementia with LBs. LBs are formed by the conversion of soluble monomers of alpha-synuclein into insoluble aggregates. Here we report an abnormal electrophoretic mobility, at a higher molecular weight (MW) than the expected theoretical MW, of both recombinant histidine-tagged human alpha-synuclein, human alpha-synuclein expressed in SH-SY5Y human neuroblastoma cells or Ltk(-) fibroblasts, and rat brain alpha-synuclein, on SDS-PAGE polyacrylamide, but not on Nu-PAGE gradient peptide, gels, suggesting possible alpha-synuclein data misinterpretations associated with gel electrophoresis.

D1 dopamine receptor mediates dopamine-induced cytotoxicity via the ERK signal cascade.

Postsynaptic striatal neurodegeneration occurs through unknown mechanisms, but it is linked to high extracellular levels of synaptic dopamine. Dopamine-mediated cytotoxicity of striatal neurons occurs through two distinct pathways: autoxidation and the D1 dopamine receptor-linked signaling pathway. Here we investigated the mitogen-activated protein kinase (MAPK) signaling pathways activated upon the acute stimulation of D1 dopamine receptors.

Ciliary neurotrophic factor increases the survival of magnocellular vasopressin and oxytocin neurons in rat supraoptic nucleus in organotypic cultures.

Organotypic cultures of the rat hypothalamus are very useful models for the long-term study of parvocellular vasopressin (VP) neurons in the paraventricular (PVN) and suprachiasmatic (SCN) nuclei. However, they do not preserve significant numbers of VP magnocellular neurons (VP-MCNs) in either the PVN or the supraoptic nucleus (SON). Vutskits et al.