P2X1 receptors and adrenoceptors are mainly responsible for vasoconstriction in a variety of blood vessels. However, previous studies have shown that α,β-methylene adenosine 5′-triphosphate (α,β-MeATP), a stable analogue of ATP, can induce both pressor and depressor responses in laboratory animals. In this study, the effects of increasing intravenous doses of α,β-MeATP and noradrenaline (NA) (0–30 nmol/kg) administered at 20 min intervals on systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure in groups of anesthetized mice (n=6) were compared. Both α,β-MeATP and NA caused transient, dose-dependent increases in SBP, DBP and MBP but the effect of α,β-MeATP was more rapid and significantly larger at doses of 10 and 30 nmol/kg (P<0.01). At the dose of 30 nmol/kg, α,β-MeATP increased SBP, DBP and MBP by 65.8±7.0, 65.7±5.0 and 65.7±5.5 mmHg, respectively, compared to increases of 36.8±4.6, 33.3±4.9 and 34.5±4.7 mmHg, respectively, produced by NA. These results indicate P2X1 receptors play an important role in BP regulation although purinergic vasoconstriction alone may not explain the more potent pressor response to α,β-MeATP in the anesthetized mouse.
Abstract Deep brain stimulation (DBS) is a well-established and effective treatment for patients with advanced Parkinson's disease (PD), yet its underlying mechanisms remain enigmatic. Optogenetics, primarily conducted in animal models, provides a unique approach that allows cell type- and projection-specific modulation that mirrors the frequency-dependent stimulus effects of DBS. Opto-DBS research in animal models plays a pivotal role in unraveling the neuronal and synaptic adaptations that contribute to the efficacy of DBS in PD treatment. DBS-induced neuronal responses rely on a complex interplay between the distributions of presynaptic inputs, frequency-dependent synaptic depression, and the intrinsic excitability of postsynaptic neurons. This orchestration leads to conversion of firing patterns, enabling both antidromic and orthodromic modulation of neural circuits. Understanding these mechanisms is vital for decoding position- and programming-dependent effects of DBS. Furthermore, patterned stimulation is emerging as a promising strategy yielding long-lasting therapeutic benefits. Research on the neuronal and synaptic adaptations to DBS may pave the way for the development of more enduring and precise modulation patterns. Advanced technologies, such as adaptive DBS or directional electrodes, can also be integrated for circuit-specific neuromodulation. These insights hold the potential to greatly improve the effectiveness of DBS and advance PD treatment to new levels.
Multiple cell death is involved in ischemic brain injury. Necroptosis, a recently reported cell death, may be the most suitable cell death mechanism in a subpopulation of neurons under ischemic injury. It reported that a small molecule, necrostatin-1 (Nec-1), has a potent inhibitory effect on necroptotic cell death in vivo and in vitro. The aim of the current study was to investigate the role of Nec-1 on cognitive function in chronic ischemic stroke mice induced by bilateral common carotid artery stenosis (BCAS). Here, 12-week-old C57BL/6 mice received intragastric administration with Nec-1 or vehicle for two weeks after stroke, and then, the effect and possible mechanism were determined. We demonstrated that inhibition of necroptosis prevented cognitive impairment and reduced inflammatory response in the ischemic brain injury mouse model. These data suggested that inhibition of necroptosis provided a potential therapeutic option for cognitive rehabilitation in chronic ischemic stroke.
Objective
To explore the function of Nod-like receptor protein 3 (NLRP3) inhibitor Mcc950 on the dendritic spine.
Methods
Establishing traumatic brain injury mouse model via pressure hitting in 60 C56BL/6J adult mice, then average the mice into three different groups based on manage process after brain injury: group control, group with normal saline, group Mcc950. After 8 months, detect the dendritic spine by Golgi-Cox staining and detect the dendritic spine regulatory protein by Western Blot.
Results
The number of 30 μm dendritic spine in group Mcc950 (32.08±1.831) is higher than group control (20.82±2.252) and group normal (19.38±1.623) saline significantly (group control vs group Mcc950: t=3.921, P=0.0007; group normal saline vs group Mcc950: t=5.187, P<0.0001). The expression level of dendritic regulatory protein PSD95, Profilin1 and GTPase HRAS are higher in group Mcc950 than group control and group normal saline, the difference is significantly (The times of expression level group Mcc950 compare to group control and group normal saline of these protein are: PSD95: 4.64, 4.34; Profilin1: 4.43, 4.47; GTPase HRAS: 2.97, 3.03. PSD95: group control vs group Mcc950: t=8.880, P=0.012, group normal saline vs group Mcc950: t=7.248, P=0.002; Profilin1: group control vs group Mcc950: t=6.654, P=0.022; group normal saline vs group Mcc950: t=5.340, P=0.033; GTPase HRAS: group control vs group Mcc950: t=5.092, P=0.036, group normal saline vs group Mcc950: t=4.469, P=0.047).
Conclusion
Mcc950, a NLRP3 inhibitor, plays a protective role in dendritic spine number after traumatic brain injury in mice.
Key words:
Mcc950; Inflammasome; Nod-like receptor protein 3; Dendritic spine
Early exercise after stroke promoted angiogenesis and increased microvessles density. However, whether these newly formatted vessels indeed give rise to functional vascular and improve the cerebral blood flow (CBF) in impaired brain region is still unclear. The present study aimed to determine the effect of early exercise on angiogenesis and CBF in ischemic region.Adult male Sprague Dawley rats were subjected to 90 min middle cerebral artery occlusion(MCAO)and randomly divided into early exercise and non-exercised control group 24 h later. Two weeks later, CBF in ischemic region was determined by laser speckle flowmetry(LSF). Meantime, micro vessels density, the expression of tie-2, total Akt and phosphorylated Akt (p-Akt), and infarct volume were detected with immunohistochemistry, 2,3,5 triphenyltetrazolium chloride (TTC) staining and western blotting respectively. The function was evaluated by seven point's method.Our results showed that CBF, vessel density and expression of Tie-2, p-Akt in ischemic region were higher in early exercise group compared with those in non-exercise group. Consistent with these results, rats in early exercise group had a significantly reduced infarct volume and better functional outcomes than those in non-exercise group.Our results indicated that early exercise after MCAO improved the CBF in ischemic region, reduced infarct volume and promoted the functional outcomes, the underlying mechanism was correlated with angiogenesis in the ischemic cortex.
Exercise training is a neuroprotective strategy in cerebral ischemic injury, but the underlying mechanisms are not yet clear. In the present study, we investigated the effects of treadmill exercise pretreatment on the expression of mitochondrial dynamic proteins. We examined the expression of OPA1/DLP1/MFF/Mfn1/Mfn2, which regulatesmitochondrial fusion and fission, and cytochrome C oxidase subunits (COX subunits), which regulatemitochondrial functions, after middle cerebral artery occlusion (MCAO) in rats. T2-weighted magnetic resonance imaging (MRI) was evaluated as indices of brain edema after ischemia as well. Treadmill training pretreatment increased the expression levels of OPA1 and COXII/III/IV and alleviated brain edema, indicating that exercise pretreatment provided neuroprotection in cerebral ischemic injury via the regulation of mitochondrial dynamics and functions.
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