Involvement of the α<Subscript>1D</Subscript>-adrenergic Receptor in Methamphetamine-Induced Hyperthermia and Neurotoxicity in Rats

Methamphetamine (METH) is a psychostimulant that damages nigrostriatal dopaminergic terminals, primarily by enhancing dopamine and glutamate release. α₁-adrenergic receptor (AR) subtype involved in METH-induced neurotoxicity in rats was investigated using selective α₁-AR antagonists. METH neurotoxicity was evaluated by (1) measuring body temperature; (2) determining tyrosine hydroxylase (TH) immunoreactivity levels; (3) examining levels of dopamine and its metabolites; and (4) assessing glial fibrillary acidic protein (GFAP) and microglial immunoreactivity in the striatum. METH caused a decrease in dopamine and TH levels and induced hyperthermia which is an exacerbating factor of METH neurotoxicity. Concurrently, METH increased GFAP expression and the number of activated microglia. Pretreatment with prazosin, a nonselective α₁-AR antagonist, completely abolished METH-induced decrease in both dopamine and TH and caused a partial reduction in hyperthermia. Prazosin also prevented METH-induced increase in both GFAP expression and the number of activated microglia. In vivo microdialysis analysis revealed that prazosin, however, does not alter the METH-induced dopamine release in the striatum. The neuroprotective effects of prazosin could be mimicked by a selective α_1D antagonist, BMY 7378, but not by selective α_1A or α_1B antagonists. These results suggest that the α_1D-AR is involved in METH-induced hyperthermia and neurotoxicity in rats.     

Changes in the mRNA Levels of α<Subscript>2A</Subscript> and α<Subscript>2C</Subscript> Adrenergic Receptors in Rat Models of Parkinson’s Disease and <Emphasis Type="SmallCaps">l</Emphasis>-DOPA-Induced Dyskinesia

The changes in the mRNA levels of α_2A and α_2C adrenoceptors were investigated in unilateral 6-OHDA-lesioned rat model of Parkinson’s disease and l-DOPA-induced dyskinesia using in situ hybridization. In the untreated 6-OHDA-lesioned rats, α_2A expression was elevated in the locus coeruleus (160 ± 8% and 142 ± 8% in lesioned and unlesioned sides compared to the comparable side in sham-operated rats). Following long-term (21 days, twice daily) treatment with l-DOPA (25 mg/kg l-DOPA methyl ester plus benserazide 6.25 mg/kg) in 6-OHDA-lesioned rats, levels of α_2A adrenoceptor mRNA in the locus coeruleus were decreased, compared to the 6-OHDA-lesioned rats, returning to the levels of α_2A mRNA in the sham-operated rats. α_2A adrenoceptor expression was not changed in other brain regions in any treatment group. There was no change in α_2C expression in the rostral or caudal striatum in which the highest density of α_2C mRNA is present. In conclusion, the data presented in this study demonstrate an increase in α_2A adrenoceptor mRNA in the locus coeruleus in the 6-OHDA-lesioned rat model of Parkinson’s disease. In addition, the data show that repeated treatment with l-DOPA in 6-OHDA-lesioned rats, which induces dyskinesia, restores α_2A mRNA levels. These changes of α_2A mRNA expression, observed in the locus coeruleus, might be of importance to basal ganglia transmission and motor function.     

Interaction Between Ca<Subscript>v</Subscript>2.1α<Subscript>1</Subscript> and CaMKII in Ca<Subscript>v</Subscript>2.1α<Subscript>1</Subscript> Mutant Mice, <Emphasis Type="Italic">Rolling Nagoya</Emphasis>

It has been reported earlier that interactions between Ca_v2.1α₁ and calcium/calmodulin-dependent protein kinase II (CaMKII) in the presynaptic fraction and between the NMDA receptor subunit NR2B and CaMKII in the postsynaptic density (PSD) fraction are important for neuronal function. Ca_v2.1α₁, CaMKII, and NR2B are predominantly expressed in the hippocampus. To examine the above interactions and CaMKII activity in the hippocampal presynapse and PSD of Rolling Nagoya mice carrying a mutation in Ca_v2.1α₁ subunit, we performed immunoprecipitation and Western blot analyses. In the presynapse, the interaction between Ca_v2.1α₁ and CaMKII and the phosphorylation of CaMKII (at Thr286) and its substrate Synapsin I (at Ser603) were decreased in mutant mice compared to wild-type mice. In the PSD, a similar pattern was observed for the interaction between NR2B and CaMKII and the phosphorylation of CaMKII (at Thr286) and its substrate AMPA receptor subunit glutamate receptor 1 (at Ser831) between mutant and wild-type mice. Our data indicate that disruption of the interaction between Ca_v2.1α₁ and CaMKII may down-regulate presynaptic CaMKII activity and that Rolling Nagoya mice would be a useful model for examining presynaptic function.     

Fast Inactivation of Ca<Subscript>V</Subscript>2.2 Channels Is Prevented by the Gβ<Subscript>1</Subscript> Subunit in Rat Sympathetic Neurons

Voltage-dependent regulation of Ca_V2.2 channels by G-proteins is performed by the β (Gβ) subunit. Most studies of regulation by G-proteins have focused on channel activation; however, little is known regarding channel inactivation. This study investigated inactivation of Ca_V2.2 channels in superior cervical ganglion neurons that overexpressed Gβ subunits. Ca_V2.2 currents were recorded by whole-cell patch clamping configuration. We found that the Gβ₁ subunit reduced inactivation, while Gβ₅ subunit did not alter at all inactivation kinetics compared to control recordings. Ca_V2.2 current decay in control neurons consisted of both fast and slow inactivation; however, Gβ₁-overexpressing neurons displayed only the slow inactivation. Fast inactivation was restored by a strong depolarization of Gβ₁-overexpressing neurons, therefore, through a voltage-dependent mechanism. The Gβ₁ subunit shifted the voltage dependence of inactivation to more positive voltages and reduced the fraction of Ca_V2.2 channels resting in the inactivated state. These results support that the Gβ₁ subunit inhibits the fast inactivation of Ca_V2.2 channels in SCG neurons. They explain the long-observed sustained Ca²⁺ current under G-protein modulation.     

Insulin-Like Growth Factor-1 Alleviates Expression of Aβ<Subscript>1–40</Subscript> and α-, β-, and γ-Secretases in the Cortex and Hippocampus of APP/PS1 Double Transgenic Mice

To examine the effect of subcutaneous injection of insulin-like growth factor-1 (IGF-1) on the expression of the amyloid protein (Aβ_1–40), α-secretase (ADAM10), β-secretase (BACE1), and γ-secretase (PS1) in APP/PS1 double transgenic mice. APP/PS1 double transgenic mice and wild-type mice were divided into wild-type group, wild-type therapy group, transgenome group, and transgenic therapy group. Subcutaneous injection of IGF-1 (50 μg/kg day) was administered once daily to the wild-type therapy group and transgenic therapy group for 8 weeks, respectively. The expression of the Aβ_1–40 in the cortex and hippocampus was detected by immunohistochemistry 8 weeks after administration. The levels of Aβ_1–40, DAM10, BACE1, and PS1 were analysed by Western blot. The expression of the Aβ_1–40 in the cortex of the gene therapy group was significantly lower than that of the transgenome group (p?<?0.05). In APP/PS1 double transgenic mice, BACE1 expression was markedly higher in both the hippocampus (p?<?0.001, p?=?0.00009) and the cortex (p?=?0.001), compared to that of the wild-type mice. The treatment of IGF-1 markedly reduced ADAM10 expression in the hippocampus in both transgenic mice and wild-type mice (p?<?0.05), whereas the treatment mainly decreased BACE1 expression in transgenic mice but not in the wild-type mice (p?<?0.05). No significant differences in PS1 levels were detected in all groups. IGF decreased Aβ_1–40 over-expression in the cortex and hippocampus and might inhibit the damage induced by Aβ_1–40 in APP/PS1 double transgenic mice. Our study suggests that IGF-1 should inhibit Aβ production through α-secretase and β-secretase but not γ-secretase.     

Role of dopamine D<Subscript>3</Subscript> and serotonin 5-HT<Subscript>1A</Subscript> receptors in <Emphasis Type="SmallCaps">l</Emphasis>-DOPA-induced dyskinesias and effects of sarizotan in the 6-hydroxydopamine-lesioned rat model of Parkinson’s disease

Sarizotan, a 5-HT_1A agonist with additional affinity for D₃ and D₄ receptors, has been demonstrated to have anti-dyskinetic effects. The mechanism by which these effects occur is not clear. Using unilateral 6-hydroxydopamine-lesioned rats that received chronic intraperitoneal (ip) administration of l-3,4-dihydroxyphenylalanine (l-DOPA) we investigated the involvement of D₃ and 5-HT_1A receptors in the effects of sarizotan on contraversive circling and abnormal involuntary movements (AIMs). Before sensitization by chronic l-DOPA treatment (12.5 with 3.25 mg/kg benserazide ip, twice daily for 21 days), no effect of the selective D₃ agonist, PD128907 (1 or 3 mg/kg ip), or the selective D₃ antagonist, GR103691 (0.5 or 1.5 mg/kg ip), was observed. Treatment with sarizotan (1 or 5 mg/kg ip) dose-dependently inhibited the l-DOPA-induced contraversive turning and AIMs. In co-treatment with the 5-HT_1A antagonist, WAY100635 (1 mg/kg ip), sarizotan failed to affect this behaviour, confirming the prominent 5-HT_1A receptor-mediated mechanism of action. In the presence of PD128907 (3 mg/kg ip), the effects of sarizotan on contraversive turning, locomotive dyskinesia and axial dystonia, but not on orolingual and forelimb dyskinesia, were blocked. On its own, PD128907 had no effect on the behavioural effects of l-DOPA except that it tended to reduce orolingual and forelimb dyskinesia. GR103691 had no effect on its own or in combination with sarizotan. These data identify an involvement of D₃ receptors in the action of sarizotan on some, but not all l-DOPA-induced motor side effects. This selective involvement is in contrast to the more general involvement of 5-HT_1A receptors in the anti-dyskinetic effects of sarizotan.     

The role of phospholipase A<Subscript>2</Subscript> in neuronal homeostasis and memory formation: implications for the pathogenesis of Alzheimer’s disease

Summary. Phospholipase A₂ (PLA₂) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA₂ activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent ³¹P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA₂ activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA₂ has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA₂ inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory. Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical and hippocampal neurons, the inhibition of PLA₂ precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken together, these findings reinforce the involvement of PLA₂ enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA₂ activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD.     

Tau protein and beta-amyloid<Subscript>1-42</Subscript> CSF levels in different phenotypes of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder with highly heterogeneous clinical manifestations. This fact has prompted many attempts to divide PD patients into clinical subgroups. This could lead to a better recognition of pathogenesis, improving targeted treatment and the prognosis of PD patients. The aim of the present study was to obtain cerebrospinal fluid (CSF) samples in PD patients and to search for a relationship between neurodegenerative CSF markers (tau protein, beta-amyloid_1-42 and index tau protein/beta-amyloid_1-42) and the clinical subtypes. PD patients were divided into three subgroups: early disease onset (EDO), tremor-dominant PD (TD-PD), and non-tremor dominant PD (NT-PD) according to the previously published classification. Neurodegenerative markers in the CSF were assessed in these three groups of patients suffering from PD (EDO-17, TD-15, NT-16 patients) and in a control group (CG) of 19 patients suffering from non-degenerative neurological diseases and 18 patients with Alzheimer’s disease (AD). The NT-PD patients were found to have significantly higher levels of CSF tau protein and index tau/beta than the control subjects and other Parkinsonian subgroups, but no significant differences in these markers were found between AD and NT-PD patients. In the context of more rapid clinical progression and more pronounced neuropathological changes in the NT-PD patient group, our results corroborate the opinion that CSF level of tau protein may be regarded as a potential laboratory marker of the presence and severity of neurodegeneration.     

An antihypokinesic action of <Emphasis Type="Bold">α</Emphasis><Subscript>2</Subscript>-adrenoceptors upon MPTP-induced behaviour deficits in mice

The effects of co-administration of either the dopamine precursor, L-Dopa, or the directly-acting, mixed dopamine (DA) agonist, apomorphine, with the alpha-adrenoceptor agonists, clonidine and guanfacine, upon the motor activity of hypoactive L-Dopa-tolerant MPTP-treated C57 BL/6 mice were measured in four experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered eight-to-ten weeks before behavioural testing. It was found that clonidine co-administered with L-Dopa (20 mg/kg) restored motor activity in a dose- and parameter-related manner: locomotion and total activity were restored by the 1 mg/kg dose, rearing behaviour by the 0.3 and 1 mg/kg doses. The restorative effects of clonidine (1 mg/kg), co-administered with L-Dopa, were antagonised completely by pretreatment with yohimbine (1 mg/kg), but not by prazosin (1 mg/kg). Guanfacine (1 mg/kg) co-administered with L-Dopa (20 mg/kg) restored locomotor, but not rearing, behaviour in L-Dopa-tolerant MPTP-treated mice. The antikinesic action of guanfacine was antagonised completely by yohimbine (1 mg/kg), but not prazosin (1 mg/kg). Clonidine (1 or 3 mg/kg) co-administered with apomorphine (0.1, 0.3, 1.0 or 3.0 mg/kg), directly-acting DA agonist, did not restore motor behaviour in the hypokinesic L-Dopa-tolerant MPTP-treated mice. Nor did apomorphine, by itself, affect the motor activity of these animals. Neurochemical analysis indicated marked DA, DOPAC and HVA depletions in the striatum, and to a much lesser extent in the frontal cortex, of MPTP-treated mice. The synergistic antiparkinsonian action of clonidine with L-Dopa, but not apomorphine, in hypokinetic MPTP mice for the restoration of responding to a suprathreshold dose of L-Dopa, to which "wearing-off" had been induced previously, is discussed.     

Interference of α-Synuclein Uptake by Monomeric β-Amyloid<Subscript>1–40</Subscript> and Potential Core Acting Site of the Interference

Increasing evidence suggests an important role of alpha-synuclein (α-Syn) in the pathogenesis of Parkinson’s disease (PD). The inter-neuronal spread of α-Syn via exocytosis and endocytosis has been proposed as an explanation for the neuropathological findings of PD in sub-clinical and clinical phases. Therefore, interfering the uptake of α-Syn by neurons may be an important step in slowing or modifying the propagation of the disease. The purposes of our study were to investigate if the uptake of α-Syn fibrils can be specifically interfered with monomeric β-Amyloid_1–40 (Aβ₄₀) and to characterise the core acting site of interference. Using a radioisotope-labelled uptake assay, we found an 80 % uptake reduction of α-Syn fibrils in neurons interfered with monomeric Aβ₄₀, but not β-Amyloid_1–42 (Aβ₄₂) as compared to controls. This finding was further confirmed by enzyme-linked immunosorbent assay (ELISA) with α-Syn uptake reduced from about 80 % (Aβ₄₂) to about 20 % (Aβ₄₀) relative to controls. To define the region of Aβ₄₀ peptide capable of the interference, we explored shorter peptides with less amino acid residues from both the C-terminus and N-terminus. We found that the interference effect was preserved if amino acid residue was trimmed to position 11 (from N-terminus) and 36 (from C-terminus), but dropped off significantly if residues were trimmed beyond these positions. We therefore deduced that the “core acting site” lies between amino acid residue positions 12–36. These findings suggest α-Syn uptake can be interfered with monomeric Aβ₄₀ and that the core acting site of interference might lie between amino acid residue positions 12–36.     

Receptor–receptor interactions involving adenosine A<Subscript>1</Subscript> or dopamine D<Subscript>1</Subscript> receptors and accessory proteins

Summary. The molecular basis for the known intramembrane receptor–receptor interactions among heptahelical receptors (G protein coupled receptors, GPCR) was postulated to be heteromerization based on receptor subtype specific interactions between different types of homomers of GPCR. Adenosine and dopamine receptors in the basal ganglia have been fundamental to demonstrate the existence of receptor heteromers and the functional consequences of such molecular interactions. The heterodimer is only one type of heteromeric complex and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist, assisting in the process of linking the GPCR and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for learning and memory. Heteromerization of D₂ dopamine and A_2A adenosine receptors is reviewed by Fuxe in another article in this special issue. Here, heteromerization between D₁ dopamine and A₁ adenosine receptors is reviewed. Heteromers formed by dopamine D₁ and D₂ receptors and by adenosine A₁ and A_2A receptors also occur in striatal cells and open new perspectives to understand why two receptors with apparently opposite effects are expressed in the same neuron and in the nerve terminals. The role of accessory proteins also capable of interacting with receptor–receptor heteromers in regulating the traffic and the molecular physiology of these receptors is also discussed. Overall, the knowledge of the reason why such complex networks of receptor–receptor and receptor–protein interactions occur in striatal cells is crucial to develop new strategies to combat neurological and neuropsychiatric diseases.     

New molecular targets for antiepileptic drugs: α<Subscript>2</Subscript>δ, SV2A,and K<Subscript>v</Subscript>7/KCNQ/M potassium channels

Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on γ-aminobutyric acid-mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: α₂δ, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development); and K_v7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves as the target for the investigational AEDs retigabine and ICA-105665. Functionally, all of the new targets modulate neurotransmitter output at synapses, focusing attention on presynaptic terminals as critical sites of action for AEDs.     

Serum α<Subscript>1</Subscript>-antitrypsin level and phenotype associated with familial moyamoya disease

Background Obstructive vascular lesions at the terminal portion of the internal carotid arteries are thought to be the primary and essential lesions in moyamoya disease. The etiology remains unknown. To detect possible mediators of the thickened intima of moyamoya disease, we measured serum alpha-1-antitrypsin (1-AT) levels and characterized the phenotype of patients with familial moyamoya disease.Patients and methods Fifty-six individuals were examined, including 29 patients with moyamoya disease from 14 families. Serum 1-AT levels were analyzed by electroimmunoassay and genomic phenotype by isoelectric focusing.Results All individuals had a normal 1-AT phenotype. The average serum 1-AT level in moyamoya disease patients was significantly higher than that of normal individuals, although both were within the normal range.Conclusions These findings suggest that serum 1-AT level may be a marker, rather than an etiologic factor, indicating the progression of moyamoya disease.     

Platelet phospholipase A<Subscript>2</Subscript> activity in patients with Alzheimer’s disease,vascular dementia and ischemic stroke

Summary Phospholipase A₂ (E.C. 3.1.1.4, PLA₂) plays an essential role in metabolism of membrane phospholipids, it is related to inflammatory reactions, secretion of amyloid precursor protein and activation of NMDA receptor after ischemia. In the present study we investigated PLA₂ activity in platelets from 37 Alzheimer’s disease (AD) patients, 32 vascular dementia (VaD) patients and 32 individuals with ischemic stroke as compared to 27 healthy elderly controls. PLA₂ activity was determined using radiometric assay. Mean platelet PLA₂ activity was increased in individuals with Alzheimer’s disease (p < 0.001). In VaD group the enzyme activity was between the values in AD and controls, these differences being significant from both groups. In the group of patients with ischemic stroke mean PLA₂ activity was higher either 48 h after the stroke or 7 days later (in both cases p < 0.001). The results may be particularly interesting in light of the fact, that inhibitors of PLA₂ activity are known.     

Periodic Variation of AAK1 in an Aβ<Subscript>1–42</Subscript>-Induced Mouse Model of Alzheimer’s Disease

Inhibition of endocytosis in an Alzheimer’s disease (AD) model has been shown to be able to prevent amyloid β (Aβ)-induced damage and to exert a beneficial effect in treating AD. Adaptor-associated kinase 1 (AAK1), which binds to the adaptor protein complex 2 (AP-2), regulates the process of clathrin-mediated endocytosis. However, how AAK1 expression varies over the course of AD is unknown. In this study, we investigated AAK1 levels in AD model mice over time. Aβ_1–42 was used to establish a mouse AD model, and the Morris water maze test was used to characterize the time course of Aβ_1–42-induced cognition changes. ELISA was used to determine AAK1 levels in plasma and Aβ_1–42 levels in brain tissues. Subsequently, the protein or gene levels of AAK1, AP-2, and Rab5 (an early endosome marker) were tested in each group. The cognitive function of Aβ_1–42-induced mice was significantly declined compared to control group, and the deficits reached a peak on day 14, but partly recovered on day 30. Moreover, the level of Aβ_1–42 detected with ELISA was highest on day 14, but reduced on day 30, paralleling the cognitive changes in the mice in our study. AAK1, AP-2, and Rab5 expression showed the same periodic variation as the changes in cognition. Thus, periodic variation in AAK1 expression is closely correlated to the decline in cognition, and AAK1 might be a suitable indicator for Alzheimer’s disease.     

Platelet phospholipase A<Subscript>2</Subscript> activity in Alzheimer’s disease and mild cognitive impairment

Summary. Phospholipase A₂ (PLA₂) controls the metabolism of phospholipids in cell membranes. In the brain, PLA₂ influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (A), which are the major components of the senile plaques in Alzheimers disease (AD). Reduced PLA₂ activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA₂ activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA₂ activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA₂). PLA₂ activity was significantly lower in AD than in controls (p<0.001). Mean PLA₂ activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA₂ activity was significantly correlated with a worse cognitive performance both at the MMSE (p=0.001) and the cognitive sub-scale of the CAMDEX inventory (p=0.002). Our data replicate previous findings of reduced platelet PLA₂ activity in AD. Both reduced PLA₂ activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA₂ inhibits the physiological secretion of the APP, a mechanism that increases A formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA₂ values in platelets would be at a higher risk to develop AD during a longitudinal follow up.     

IRF-8 is Involved in Amyloid-β<Subscript>1–40</Subscript> (Aβ<Subscript>1–40</Subscript>)-induced Microglial Activation: a New Implication in Alzheimer’s Disease

Using microarray analysis, we detected microRNA-124 (miR-124) to be abundantly expressed in the olfactory bulb (OB). miR-124 regulates adult neurogenesis in the subventricular zone (SVZ). However, much less is known about its role in newborn OB neurons. Here, using both gain-of-function and loss-of-function approaches, we demonstrate that brain-specific miR-124 affects dendritic morphogenesis and spine density in newborn OB neurons. Functional Annotation Clustering of miR-124 targets was enriched in “cell morphogenesis involved in neuron differentiation.”     

Increased infections with β-blocker use in ischemic stroke,a β<Subscript>2</Subscript>-receptor mediated process?

Strokes promote immunosuppression, partially from increased sympathetic activity. Altering sympathetic drive with β-blockers has variably been shown to improve stroke outcomes. This study adds to this literature using propensity score matching to limit confounding and by examining the effects of selective and non-selective β-blockers. Prospective data from acute ischemic stroke admissions at a single center from July 2010–June 2015 were analyzed. Outcomes included infection (urinary tract infection [UTI], pneumonia, or bacteremia), discharge modified Rankin Score (mRS), and in-hospital death. Any selective and non-selective β-blocker use during the first 3 days of admission were investigated with propensity score matching. A sensitivity analysis was also performed. This study included 1431 admissions. Any β-blocker use was associated with increased infections (16.4 vs. 10.7%, p = 0.030). Non-selective β-blocker use was associated with increased infections (18.9 vs. 9.7%, p = 0.005) and UTIs (13.0 vs. 5.5%, p = 0.009). Selective β-blocker use was not associated with infection. There were no associations between β-blocker use and in-hospital death or discharge mRS. In the sensitivity analysis, the association between non-selective β-blocker use and urinary tract infections persisted (12.5 vs. 4.2%, p = 0.044). No associations with death or mRS were found. Early β-blocker use after ischemic stroke may increase the risk of infection but did not change disability or mortality risk. The mechanism may be mediated by β₂-adrenergic receptor antagonism given the different effects seen with selective versus non-selective β-blocker use.     

Receptor–receptor interactions in central cardiovascular regulation. Focus on neuropeptide/α<Subscript>2</Subscript>-adrenoreceptor interactions in the nucleus tractus solitarius

Summary. The nucleus tractus solitarii (NTS) is a key nucleus in central cardiovascular control. In this mechanism it is well known the role of the α₂-adrenoreceptors for the modulation of the autonomic pathways. Moreover a number of neuropeptides described in the NTS, including Neuropeptide Y (NPY), Galanin (GAL) and Angiotensin II (Ang II), have different roles in regulating the cardiovascular function within this nucleus. We show in this review several data which help to understand how these neuropeptides (NPY, GAL and Ang II) could modulate the cardiovascular responses mediated through α₂-adrenoreceptors in the NTS. Also we show for the first time the interactions between neuropeptides in the brain, specifically the interactions between NPY, GAL, and Ang II, and its functional relevance for central cardiovascular regulation. These data strength the role of neuropeptides on central autonomic control and provide some evidences to understand the neurochemical mechanisms involved in the cardiovascular responses from the NTS.