Neuroscience
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Spike and wave discharges (SWDs), generated within cortico-thalamo-cortical networks, are the electroencephalographic biomarker of absence epilepsy. The current work aims to identify mechanisms of SWD initiation, maintenance and termination by the analyses of dynamics and directionality of mutual interactions between the neocortex and various functionally different thalamic nuclei. ⋯ The initiation of SWD is due to a gradual increase in intracortical coupling, followed by a selective increase in first unidirectional and later bidirectional coupling between the cortex and thalamus and also intrathalamically. Once the network is oscillating, coupling decreases in most of the channel pairs, although the cortex keeps its influence on the cRTN. The SWD is dampened by a gradual increase in coupling strength and in the number of channel pairs that influence each other; the latter might represent an endogenous brake of SWDs.
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Microglial activation results in profound morphological, functional and gene expression changes that affect the pro- and anti-inflammatory mechanisms of these cells. Although statins have beneficial effects on inflammation, they have not been thoroughly investigated for their ability to affect microglial functions. Therefore the effects of rosuvastatin, one of the most commonly prescribed drugs in cardiovascular therapy, either alone or in combination with bacterial lipopolysaccharide (LPS), were profiled in pure microglial cultures derived from the forebrains of 18-day-old rat embryos. ⋯ Finally, rosuvastatin beneficially and differentially affected the expression of a number of inflammation-related genes in LPS-challenged cells by inhibiting numerous pro-inflammatory and stimulating several anti-inflammatory genes. Since the microglia could elicit pro-inflammatory responses leading to neurodegeneration, it is important to attenuate such mechanisms and promote anti-inflammatory properties, and develop prophylactic therapies. By beneficially regulating both pro- and anti-inflammatory microglial functions, rosuvastatin may be considered as a prophylactic agent in the prevention of inflammation-related neurological disorders.
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Central blockade of mineralocorticoid receptors (MRs) or angiotensin II type 1 receptors (AT1Rs) attenuates aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR and AT1R specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats were treated with subcutaneous aldo (1μg/h) plus saline as drinking fluid, and gene expression was assessed by real-time qPCR. ⋯ SFO lesion, blockade of brain AS or MR, or knockdown of MR or AT1R in the PVN similarly attenuated aldosterone-induced saline intake by ∼50% and hypertension by ∼70%. These results suggest that an increase in circulating aldosterone may via MR and AT1R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR enhance AT1R signaling in the PVN. This central aldosterone-MR-AT1R neuro-modulatory pathway appears to play a major role in the progressive hypertension.
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Following brain ischemia reperfusion (IR), the dramatic increase in adenosine activates A2AR to induce further neuronal damage. Noteworthy, A2A antagonists have proven efficacious in halting IR injury, however, the detailed downstream signaling remains elusive. To this end, the present study aimed to investigate the possible involvement of phospho-extracellular signal-regulated kinase (pERK1/2) pathway in mediating protection afforded by the central A2A blockade. ⋯ Consequent to pERK1/2 inhibition, reduced hippocampal microglial activation, glial tumor necrosis factor-alpha (TNF-α) and brain-derived neurotropic factor (BDNF) expression, glutamate (Glu), inducible nitric oxide synthase (iNOS) and thiobarbituric acid reactive substances (TBARS) were evident in animals receiving SCH58261. Additionally, the anti-inflammatory cytokine interleukin-10 (IL-10) increased following nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). Taken all together, these events suppressed apoptotic pathways via a reduction in cytochrome c (Cyt. c) as well as caspase-3 supporting a crucial role for pERK1/2 inhibition in consequent reduction of inflammatory and excitotoxic cascades as well as correction of the redox imbalance.
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Temporal lobe epilepsy in human and animals is attributed to alterations in brain function especially hippocampus formation. Changes in synaptic activity might be causally related to the alterations during epileptogenesis. Transient receptor potential vanilloid 1 (TRPV1) as one of the non-selective ion channels has been shown to be involved in synaptic transmission. ⋯ SE induced an upregulation of TRPV1 mRNA and protein content in the whole hippocampal extract, as well as its distribution in both CA1 and CA3 regions. Activation and inhibition of TRPV1 receptors (via capsaicin 1μM and capsazepine 10μM, respectively) did not influence basal synaptic transmission in CA1 and CA3 regions of control slices, however, capsaicin increased and capsazepine decreased synaptic transmission in both regions in tissues from epileptic animals. Taken together, these findings suggest that a higher expression of TRPV1 in the epileptic condition is accompanied by alterations in basal synaptic transmission.