Amelioration of central neurodegeneration by docosahexaenoic acid in trigeminal neuralgia rats through the regulation of central neuroinflammation.

Trigeminal neuralgia (TN) is a stubborn head and face neuropathic pain with complex pathogenesis. Patients with TN have a significantly increased risk of central neurodegeneration, which manifests as cognitive impairment and memory loss, but the specific mechanism underlying central nervous degeneration is still unclear. This study aimed to explore central neurodegeneration and its possible mechanism of action in TN rats based on changes in the brain fatty acid content and microglia-related neuroinflammation. Using a TN neuropathic pain model established by us, we found that TN rats have obvious cognitive impairment. Furthermore, changes in the brain fatty acid content were analyzed using gas chromatography-mass spectrometry (GC-MS). It was found that the docosahexaenoic acid (DHA) content in the central nervous system (CNS) of TN rats was significantly decreased compared to that in the CNS of Sham rats. An important component in maintaining brain cognition, DHA also plays a key role in regulating central neuroinflammation. Here, by continuous supplementation of DHA, the CNS DHA content was increased to a certain extent in TN rats. The cognitive impairment of TN rats was improved after restoring the central DHA level; this may be related to the improvement of neuroinflammation through the DHA-mediated regulation of microglial polarization. Overall, this study provides a theoretical basis for explaining the pathogenesis of central neurodegeneration in TN. It also suggests DHA as a target for protecting the CNS of patients with TN from damage.

Altered gray matter volume and functional connectivity in patients with herpes zoster and postherpetic neuralgia.

Numerous neuroimaging studies on postherpetic neuralgia (PHN) and herpes zoster (HZ) have revealed abnormalities in brain structure/microstructure and function. However, few studies have focused on changes in gray matter (GM) volume and intrinsic functional connectivity (FC) in the transition from HZ to PHN. This study combined voxel-based morphometry and FC analysis methods to investigate GM volume and FC differences in 28 PHN patients, 25 HZ patients, and 21 well-matched healthy controls (HCs). Compared to HCs, PHN patients exhibited a reduction in GM volume in the bilateral putamen. Compared with HZ patients, PHN patients showed decreased GM volume in the left parahippocampal gyrus, putamen, anterior cingulate cortex, and right caudate and increased GM volume in the right thalamus. However, no regions with significant GM volume changes were found between the HZ and HC groups. Correlation analysis revealed that GM volume in the right putamen was positively associated with illness duration in PHN patients. Furthermore, lower FCs between the right putamen and right middle frontal gyrus/brainstem were observed in PHN patients than in HCs. These results indicate that aberrant GM volumes and FC in several brain regions, especially in the right putamen, are closely associated with chronification from HZ to PHN; moreover, these changes profoundly affect multiple dimensions of pain processing. These findings may provide new insights into the pathophysiological mechanisms of PHN.

NLRP3 Inflammasome Mediates Neurodegeneration in Rats with Chronic Neuropathic Pain.

ABSTRACT: Patients with chronic neuropathic pain (NP) have a significantly increased risk of central nervous degeneration. Trigeminal neuralgia (TN) is a typical NP, and this manifestation is more obvious. In addition to severe pain, patients with TN are often accompanied by cognitive dysfunction and have a higher risk of central nervous system degeneration, but the mechanism is not clear. The NOD-like receptor 3 (NLRP3) inflammasome assembles inside of microglia on activation, which plays an important role in neurodegeneration such as Alzheimer disease. MCC950 is a specific blocker of NLRP3 inflammasome, which can improve the performance of degenerative diseases. Although NLRP3 inflammasome assembles inside of microglia on activation has been shown to be essential for the development and progression of amyloid pathology, its whether it mediates the neurodegeneration caused by NP is currently unclear. By constructing a rat model of chronic TN, we found that as the course of the disease progresses, TN rats have obvious cognitive and memory deficit. In addition, Tau hyperphosphorylation and Aß expression increase in the cortex and hippocampus of the brain. At the same time, we found that NLRP3 expression increased significantly in model rats. Interestingly, NLRP3 specific blocker MCC950 can alleviate the neurodegeneration of trigeminal neuralgia rats to a certain extent. It is suggested that our NLRP3 inflammasome plays an important role in the neurodegeneration of trigeminal neuralgia rats. And it is related to the activation of central nervous system inflammation.

Oleanolic acid inhibits mouse spinal cord injury through suppressing inflammation and apoptosis via the blockage of p38 and JNK MAPKs.

Spinal cord injury (SCI) is reported as a devastating disease, leading to tissue loss and neurologic dysfunction. However, there is no effective therapeutic strategy for SCI treatment. Oleanolic acid (OA), as a triterpenoid, has anti-oxidant, anti-inflammatory, and anti-apoptotic activities. However, its regulatory effects on SCI have little to be elucidated, as well as the underlying molecular mechanisms. In this study, we attempted to explore the role of OA in SCI progression. Behavior tests suggested that OA treatments markedly alleviated motor function in SCI mice. Evans blue contents up-regulated in spinal cords of SCI mice were significantly reduced by OA in a dose-dependent manner, demonstrating the improved blood-spinal cord barrier. Moreover, we found that OA treatments significantly reduced the apoptotic cell death in spinal cord samples of SCI mice through decreasing the expression of cleaved Caspase-3. In addition, pro-inflammatory response in SCI mice was significantly attenuated by OA treatments. Furthermore, SCI mice exhibited higher activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways, but these effects were clearly blocked in SCI mice with OA treatments, as evidenced by the down-regulated phosphorylation of p38, c-Jun-NH 2 terminal kinase (JNK), IκB kinase α (IKKα), inhibitor of nuclear factor κB-α (IκBα) and NF-κB. The protective effects of OA against SCI were confirmed in lipopolysaccharide (LPS)-stimulated mouse neurons mainly through the suppression of apoptosis and inflammatory response, which were tightly associated with the blockage of p38 and JNK activation. Together, our data demonstrated that OA treatments could dose-dependently ameliorate spinal cord damage through impeding p38- and JNK-regulated apoptosis and inflammation, and therefore OA might be served as an effective therapeutic agent for SCI treatment.

Lipid emulsion mitigates local anesthesia-induced central nervous system toxicity in rats.

The aim of the present study was to investigate the effect of intravenously administered lipid emulsion on local anesthetic (LA)-induced central nervous system (CNS) toxicity. A total of 100 male Sprague Dawley rats were allocated at random into the following groups: Sham (A), lidocaine (B), levobupivacaine (C) and ropivacaine (D). Groups B-D were each subdivided into three subgroups: Toxic, post-conditioning and pre-conditioning. Intracerebroventricular injections of 0.9% normal saline (sham group) or LA were administered via microsyringe; in addition, a 20% lipid emulsion was injected into tail vein prior to the LA injection (pre-conditioning subgroups) or following rat respiratory arrest (post-conditioning subgroups). The heart rate, blood pressure, neurological behavior scores, neuronal density and time from LA injection to respiratory arrest, apnea and start of arrhythmia were measured. Rats in the toxic groups died due to respiratory arrest following the injection of LA into the lateral ventricle. Rats in the post-conditioning subgroups were resuscitated from the LA-induced respiratory arrest, while the pre-conditioning subgroup rats exhibited no respiratory arrest. No significant differences in heart rate were observed between the toxic and post-conditioning subgroups in the levobupivacaine and ropivacaine groups (P>0.05); however, a significant difference was observed between these treatment groups and the rats treated with lidocaine (P<0.01). A significant difference was also observed in the time from the LA injection to the onset of arrhythmia among the rats in groups B, C and D (P<0.01). No significant differences in the neurological behavior scores and neuronal density were observed in the hippocampal CA1 zone among group C and D rats in the post- and pre-conditioning subgroups at various time-points following treatment. Beyond that, the same phenomena regarding neurological behavior scores was observed in post- and pre-conditioning subgroups of group B at 12 and 24 h treatment, contrasting with the statistically significant difference between post- and pre-conditioning subgroups at 6 h treatment (P<0.01). The results of the present study therefore indicate that pre- and post-conditioning with lipid emulsion effectively mitigates LA-induced CNS toxicity in rats.

Penehyclidine hydrochloride postconditioning on lipopolysaccharide-induced acute lung injury by inhibition of inflammatory factors in a rodent model.

BACKGROUND: Sepsis is associated with acute lung injury (ALI) and high mortality. The aim of this study was to investigate the effects of different doses of penehyclidine hydrochloride (PHC) postconditioning on ALI induced by sepsis in a rat model. METHODS: A rat model of ALI was induced by intravenous injection of lipopolysaccharide (LPS). The different doses of PHC were administrated intravenously at 30 min after LPS administration (low dose, 0.3 mg/kg; medium dose, 1.0 mg/kg, and high dose, 3.0 mg/kg). After 6 h, arterial blood samples were obtained for blood gas analyses. Meanwhile, lung tissue was harvested and lung injury was assessed by the histopathologic changes (hematoxylin and eosin staining) and wet-to-dry lung weight ratio. The tumor necrosis factor-α and interleukin-6 levels in bronchoalveolar lavage fluid, as well as the nuclear factor-kappa B protein expressions, and the myeloperoxidase activities in lung tissues were measured by immunohistochemistry or enzyme-linked immunosorbent assay, respectively. RESULTS: LPS-induced severe lung injury evidenced by increased pathologic scores and lung wet-to-dry weight ratio, which was accompanied by increases in the expression of pulmonary nuclear factor-kappa B protein and the activity of pulmonary myeloperoxidase and the levels of interleukin-6 and tumor necrosis factor-α in bronchoalveolar lavage fluid. The arterial oxygen tension (PaO2), pH, and the PaO2/fraction of inspired oxygen ratio (PaO2/FiO2) decreased significantly and the carbon dioxide tension (PaCO2) increased notedly after an LPS injection. All doses of PHC could significantly ameliorate lung injury and improve the previously mentioned variables (P < 0.05 or 0.01). Furthermore, the protection of medium dose (1.0 mg/kg) could be better than that of low or high dose. CONCLUSIONS: These findings indicated that different doses of PHC, especially to medium dose, could prevent LPS-induced ALI in rats, at least in part, by inhibiting inflammatory response. Moreover, the protection of pharmacologic postconditioning with PHC is limited by a "ceiling effect."

The experiment research of neuroprotection of hypoperfusion postconditioning on cerebral ischemia.

In this study, we tested the hypothesis that the alternating of hypoperfusion and full reperfusion (hypoperfusion postconditioning) could improve neuroprotection on cerebral ischemia in rats and explored the role of TAp63 and △Np63 in this process. Eighty male Sprague Dawley rats were randomly divided into 4 groups: the sham group, the cerebral ischemic/reperfusion group (I/R), the hypoperfusion group 1 (HR1), and the hypoperfusion group 2 (HR2). Cerebral ischemia was established by clamping the bilateral common carotid artery with hypotension for 20 minutes. For the rats in the HR1 group, the blood pressure was maintained to 80 to 90 mm Hg in clamping bilateral common carotid artery minutes and then unclamped. For the rats in the HR2 group, the clamping was performed at one side of the common carotid artery and one half of the other side of common carotid artery. Neurologic behavior scores in the I/R, HR1, and HR2 groups decreased significantly after cerebral ischemia, and scores in the HR2 group were significantly higher than those in the I/R group (P < 0.05). Neuronal densities in the HR1 and HR2 groups were significantly higher than that in the I/R group (P < 0.05). Neuronal apoptosis in the HR1 and HR2 groups was significantly lower than that in the I/R group (P < 0.05). TAp63 and S100ß concentration decreased, and △Np63 increased significantly in the HR1 and HR2 groups as compared with the I/R group (P < 0.05). No significant difference in these parameters between the HR1 and HR2 groups (P > 0.05). Alternating of hypoperfusion and normal perfusion postconditioning had neuroprotection function on cerebral ischemia in the rats. This could relate with decreasing expression of TAp63 and increasing expression of △Np63 in hippocampal region of the first area in the hippocampal circuit to inhibit neuronal apoptosis.