Pien-Tze-Huang, a Chinese patent formula, attenuates NLRP3 inflammasome-related neuroinflammation by enhancing autophagy via the AMPK/mTOR/ULK1 signaling pathway.

NLRP3 inflammasome is a key mediator in ischemic stroke-induced neuroinflammation and subsequent brain injury. Our previous study demonstrated the potent activity of Pien-Tze-Huang (PTH), a well-known Chinese patent formula, in reducing mitochondria-mediated neuronal apoptosis in cerebral ischemia/reperfusion impaired rats. This study aims to elucidate the mechanistic action of PTH related to neuroinflammation in LPS-induced BV2 microglial cells and cerebral ischemia/reperfusion impaired rats. BV2 cells were stimulated with LPS for 12 h and treated with PTH with various concentrations. Modulation by PTH of relevant genes (IL-6, IL-1ß, IL-18, TNF-α, COX-2 and iNOS mRNA) and proteins (NLRP3 inflammasome, autophagy and AMPK/mTOR/ULK signaling) was analyzed by real-time PCR and western blot, respectively. Similar analyses were conducted in middle cerebral artery occlusion rat model including neurological deficit, infarct volume, microglial activation, and key genes and proteins in modulating autophagy and NLRP3. Our results showed that PTH significantly inhibited the production of key proinflammatory mediators and protein expressions of NLRP3 and caspase-1 p20 in LPS induced BV2 cells. It also enhanced the autophagy response by modulating the key autophagy proteins via AMPK/mTOR/ULK related pathway. The reduced inflammatory responses and NLRP3 expressions by PTH were partially blocked by the autophagy inhibitor (3-MA) and AMPK blocker (compound C). In rats, PTH significantly reduced infarct size, suppressed microglial activation, and improved neuron deficit. It also promoted autophagy and reduced NLRP3 activity. Our study demonstrated that PTH inhibited NLRP3 inflammasome-mediated neuroinflammation, which was associated with enhanced autophagy via AMPK/mTOR/ULK1 pathway in vitro and in vivo.

Supplementation with ribonucleotide-based ingredient (Ribodiet®) lessens oxidative stress, brain inflammation, and amyloid pathology in a murine model of Alzheimer.

Alzheimer's disease (AD) is the most common type of dementia worldwide, characterized by the deposition of neurofibrillary tangles and amyloid-ß (Aß) peptides in the brain. Additionally, increasing evidence demonstrates that a neuroinflammatory state and oxidative stress, iron-dependent, play a crucial role in the onset and disease progression. Besides conventional therapies, the use of natural-based products represents a future medical option for AD treatment and/or prevention. We, therefore, evaluated the effects of a ribonucleotides-based ingredient (Ribodiet®) in a non-genetic mouse model of AD. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aß1-42 peptide (3 µg/3 µl) and after with Ribodiet® (0.1-10 mg/mouse) orally (p.o.) 3 times weekly for 21 days following the induction of experimental AD. The mnemonic and cognitive decline was then evaluated, and, successively, we have assessed ex vivo the modulation of different cyto-chemokines on mice brain homogenates. Finally, the level of GFAP, S100ß, and iron-related metabolic proteins were monitored as markers of reactive gliosis, neuro-inflammation, and oxidative stress. Results indicate that Ribodiet® lessens oxidative stress, brain inflammation, and amyloid pathology via modulation of iron-related metabolic proteins paving the way for its rationale use for the treatment of AD and other age-related diseases.

Gypenosides reverses depressive behavior via inhibiting hippocampal neuroinflammation.

Gypenosides, a saponins extract isolated from the Gynostemma pentaphyllum plant, produces neuroprotective effects in the brain. Our previous studies have shown that hippocampal glucocorticoid receptor (GR)-brain-derived neurotrophic factor (BDNF)-TrkB signaling was involved in the antidepressant-like effects of gypenosides. It remains unknown whether gypenosides could alleviate neuroinflammation in depressive-like animals. The aim of the present study was to address this issue in chronic unpredictable mild stress (CUMS). Gypenosides was administrated for four weeks, followed by sucrose preference test and tail suspension test, which were performed to evaluate the effects of gypenosides. The results showed that gypenosides reversed both the decreased sucrose preference and increased immobility time in CUMS mice. In addition, gypenosides also attenuated the increase of pro-inflammatory cytokine levels in the hippocampus of CUMS animals. Furthermore, the activation of NF-κB, as well as its upstream mediators IKKα and IKKß were inhibited by gypenosides. Last but not the least, CUMS promoted the activation of microglia, while gypenosides suppressed it according to the reduced number of iba1 positive cells. In conclusion, this study demonstrates that gypenosides exhibits the antidepressant-like effects in mice, which may be mediated by the inhibition of microglia and NF-κB signaling in the hippocampus.

Perioperative moxifloxacin treatment in rats subjected to deep hypothermic circulatory arrest: reduction in cerebral inflammation but without improvement in cognitive performance.

OBJECTIVE: Moxifloxacin reduces infectious complications after cerebral damage, such as ischemia and stroke. This study investigated whether moxifloxacin treatment influences cerebral inflammation and improves cognitive outcome after cardiopulmonary bypass with deep hypothermic circulatory arrest in rats. METHODS: Rats were randomly assigned to deep hypothermic circulatory arrest (n = 40), sham operation (n = 40), and untreated control (n = 20) groups. Deep hypothermic circulatory arrest and sham groups were equally subdivided into moxifloxacin and placebo subgroups, receiving 6 × 100 mg/kg moxifloxacin or saline solution every 2 hours intraperitoneally. Hippocampal tumor necrosis factor α, nuclear factor κB, cyclooxygenase 2, and macrophages were assessed immunohistochemically. Histologic outcome was determined with hematoxylin and eosin. Neurologic outcome was assessed preoperatively and postoperatively. Cognitive performance was tested with the modified hole board test for 14 postoperative days. RESULTS: On postoperative day 14, deep hypothermic circulatory arrest moxifloxacin group was lower than deep hypothermic circulatory arrest placebo group in hippocampal neurons positive for tumor necrosis factor α (1.33, 0.73-2.37, vs 4.10, 2.42-18.67), nuclear factor κB (3.03, 1.33-5.20, vs 9.32, 2.53-24.14), and cyclooxygenase 2 (3.16, 0.68-6.04, vs 8.07, 3.27-19.91) and also had fewer macrophages than all other groups (72, 60-90, vs deep hypothermic circulatory arrest placebo 128, 76-203, sham moxifloxacin 89, 48-96, and sham placebo 81, 47-87). On postoperative day 14, both deep hypothermic circulatory arrest groups showed impaired motor, cognitive, and histologic outcomes relative to sham-operated groups, with no difference between deep hypothermic circulatory arrest subgroups. CONCLUSIONS: Moxifloxacin transiently reduces cerebral inflammatory reaction, but without impact on neurologic function, histologic outcome, or long-term cognitive performance.

Transient mutism and pathologic laughter in the course of cerebellitis.

The phenomenon of cerebellar mutism with subsequent dysarthria is most commonly described as a part of posterior fossa syndrome after surgery for neoplasms in childhood. Pathologic laughter, on the other hand, is observed primarily in various neurologic diseases in adults. In the present case, a child manifested transient mutism and pathologic laughter during a severe cerebellitis. Headache, vertigo, and impaired consciousness developed during an acute respiratory infection. Thereafter, severe ataxia, mutism, and involuntary laughter became the main clinical features, as well as pyramidal signs. Magnetic resonance imaging revealed cerebellar swelling and T(2) hyperintensity. During steroid treatment, a gradual vanishing of the pathologic laughter and improvement of the motor and speech functions occurred. Recovery was slow and incomplete, and follow-up magnetic resonance imaging showed cerebellar atrophy. This case confirms that mutism is a rare, but possible, manifestation in acute parainfectious cerebellitis and provides a novel example of pathologic laughter during this disease in childhood.

Selective loss of imagery in a case of visual agnosia.

Experiments were designed to examine the imagery abilities of an agnosic patient, M.S., who has consistently shown more severe deficits in recognizing visually, and in retrieving knowledge of living as compared with non-living items. Judgements of visual similarity were required for named objects and for object-pictures, as well as for the factual properties of these stimuli. The same disproportionate difficulty in processing living ('natural') objects was found in these tasks as well as in forced-choice recognition. In contrast, no deficit was found on analogous tasks concerned with word-shape similarities. These findings have a bearing on concepts of semantic memory.

The dissociation of anterograde and retrograde amnesia in a patient with herpes encephalitis.

Establishing the precise relationship between anterograde amnesia (AA) and retrograde amnesia (RA) has implications for psychological and neuroanatomical models of memory. Many patients have been described who demonstrate AA in conjunction with RA or who demonstrate AA with little, or no apparent, RA. Intact anterograde memory in conjunction with deficits on tasks of retrograde memory is rarely encountered. In this paper, we describe a young female patient (LD) whose RA is extremely severe when contrasted with her mild to moderate deficits on tasks of verbal anterograde memory. In addition, on tests of episodic and semantic autobiographical memory, LD appeared more impaired in her recall of specific episodes than of factual information about her past. The importance of this dissociation in RA for the episodic-semantic distinction and the possible role of visual imagery in recalling remote episodic events are discussed.

[Primarily unilateral herpes encephalitis. Long-term neuropsychological study of 9 cases]. / Encéphalites herpétiques à prédominance unilatérale. Etude neuropsychologique au long cours de 9 cas.

Nine cases of post-herpetic encephalitis with predominant involvement of one temporal lobe at CT scan or MRI (6 on the left and 3 on the right sides) were studied 1 to 6 years after onset with repeated language and memory testing. The neuropsychological findings were well correlated with the lateralization and size of the lesions, as previously observed in unilateral temporal lobectomy. Compared with the usual bilateral form, the sequelae were mild, and all the patients, especially those with right hemisphere involvement, resumed a subnormal family life or social activity. In patients with left predominant lesions the anterograde amnesia concerned verbal information, especially logical and abstract, without visual amnesia. In some cases, the episodic verbal amnesia was associated with a semantic deficit which included the knowledge of some words. In one patient the colour, use and mental imagery of some objects corresponding to forgotten words were involved only for some specific groups (natural objects, whereas man-made objects fared better). Testing of verbal memory is proposed to determine the role of the preserved minor hemisphere in learning the context of word presentation, and words with concrete and visual connections which are better recalled than those with abstract or logical link. Disorders of behaviour or mood are usual in the 2 groups of lesions. Thus, herpes encephalitis in these asymmetrical and benign forms in an attractive model to study the role played by the temporal lobe and lateralization in memory.

Problems in the acquisition of imagery mnemonics: three brain-damaged cases.

The literature provides little direction on how to overcome difficulties which some brain-damaged patients have in acquiring imagery mnemonics as a memory aid during the period of anterograde amnesia. For those interested in the therepeutic usefulness of imagery mediation, we provide a detailed account of the acquisition of some mnemonic skill in three brain-damaged patients who initially failed in using visual imagery mediators to recall words lists.