Urolithin A alleviates blood-brain barrier disruption and attenuates neuronal apoptosis following traumatic brain injury in mice

Urolithin A(UA)is a natural metabolite produced from polyphenolics in foods such as pomegranates,berries,and nuts.UA is neuroprotective against Parkinson’s disease,Alzheimer’s disease,and cerebral hemorrhage.However,its effect against traumatic brain injury remains unknown.In this study,we established adult C57BL/6J mouse models of traumatic brain injury by controlled cortical impact and then intraperitoneally administered UA.We found that UA greatly reduced brain edema;increased the expression of tight junction proteins in injured cortex;increased the immunopositivity of two neuronal autophagy markers,microtubule-associated protein 1A/B light chain 3A/B(LC3)and p62;downregulated protein kinase B(Akt)and mammalian target of rapamycin(mTOR),two regulators of the phosphatidylinositol 3-kinase(PI3K)/Akt/mTOR signaling pathway;decreased the phosphorylation levels of inhibitor of NFκB(IκB)kinase alpha(IKKα)and nuclear factor kappa B(NFκB),two regulators of the neuroinflammation-related Akt/IKK/NFκB signaling pathway;reduced blood-brain barrier permeability and neuronal apoptosis in injured cortex;and improved mouse neurological function.These findings suggest that UA may be a candidate drug for the treatment of traumatic brain injury,and its neuroprotective effects may be mediated by inhibition of the PI3K/Akt/mTOR and Akt/IKK/NFκB signaling pathways,thus reducing neuroinflammation and enhancing autophagy.

The gap junction blocker carbenoxolone enhances propofol and sevoflurane-induced loss of consciousness

General anesthetics induce loss of consciousness by inhibiting ascending arousal pathways, and they interfere with gap junction electrical coupling. The present study aimed to determine whether inhibition of gap junction-mediated signaling could influence general anesthetic-induced loss of consciousness. The general anesthetics sevoflurane and propofol were used. Intracerebroventricular administration of carbenoxolone, a gap junction blocker, significantly decreased the time to loss of the righting reflex （P 0.05）, but prolonged the time to recovery of the reflex （P 0.05）. Moreover, intracerebroventricular administration of carbenoxolone increased the sensitivity to sevoflurane, with a leftward shift of the loss of righting reflex dose-response curve, and decreased the 50% effective concentration of sevoflurane. These results suggest that the gap junction blocker carbenoxolone enhances propofol and sevoflurane-mediated general anesthesia.

Morphine pre-exposure facilitates reinstatement but attenuates retention of morphine-induced place preference

BACKGROUND： Drug-associated conditioned stimuli are a key factor to induce morphine relapse. To date, limited evidence is available regarding the impact of drug history on propensity or vulnerability to relapse after long-term abstinence. OBJECTIVE： To determine the effect of morphine pre-exposure on acquisition, maintenance and reinstatement of morphine-induced conditioned place preference （CPP） in rats. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Laboratory of Behavior Pharmacology, Institute of Psychology, the Chinese Academy of Sciences, from March to September, 2006. MATERIALS： Morphine hydrochloride was purchased from Qinghai Pharmaceutical, China; CPP software was designed and developed by Taiji Software Company, Beijing, China. METHODS： A total of 64 Sprague Dawley rats were randomly assigned to eight groups （n = 8）. Four morphine pretreatment regimens were used （subcutaneous injections, twice daily for 5 consecutive days and a total of 10 times）： （1） ＂intensive＂ （morphine injections with doses escalating from 10 to 60 mg/kg; （2） ＂moderate＂ （one morphine injection at 5 mg/kg dose and one saline injection at 1 mL/kg daily for 5 days）; and （3） ＂single＂ （nine saline injections at 1 mL/kg followed by one morphine injection at 5 mg/kg; （4） control （ten saline injections at 1 mL/kg）. At 5 days after morphine pretreatment, animals were divided into two subgroups that underwent morphine conditioned or saline conditioned training. The test for acquisition of CPP was performed 24 hours after CPP training. The retention of morphine CPP was measured by repeated tests performed weekly for 1 month after the initial test of place preference. After extinction by pairing each chamber with saline, the reinstatement of place preference by low doses of morphine （0.05, 0.15, 0.45 mg/kg） was tested. MAIN OUTCOME MEASURES： Acquisition, maintenance, and recovery response of CPP behavior. RESULTS： The acquisition magnitude of morphine-induced CPP was not affected by prior morphine exposure （F3, 56=0.17, P 〉 0.05）. However, rats treated with moderate or intensive morphine pretreatment showed a less persistent CPP （t = -1.36, P 〉 0.05; t = -1.18, P 〉 0.05）, but their place preference was reinstated by a low dose of morphine priming （t = -2.55, P 〈 0.05; t = -2.54, P 〈 0.05）. The retention and reinstatement of morphine-induced CPP did not differ between rats with single morphine pre-exposure and control rats. CONCLUSION： Morphine pretreatment enhanced reinstatement of morphine-induced CPP but with less persistence. Individuals with heavy drug exposure are more susceptible to drug relapse when re-exposed to addictive drugs.

How Do We Have Feelings?

For centuries, the question of how a physical structure (the brain) generates the subjective feeling of consciousness has plagued neuroscientists, physiologists, psychologists, linguists, and philosophers. This has become known as the “hard problem of consciousness” and has been the subject of many publications. Although lots of answers have been proposed, none has been completely satisfactory. The focus of most of these studies has been on the neuronal structures and activities. Experiential consciousness emerges from neural processes, but it has not been explained with models that have been based solely on the electro-mechanical aspects of the processes. There must be some other dynamic features of neuronal activity to explain the emergence of experiential consciousness. I argue that a likely answer to the dilemma resides in the added dimension of the neurochemistry of the brain that has, so far, received little attention.

Advances in Oligoprotection

Oligodendrocytes, the myelinating glial cells of the nervous system, in various disease states display great vulnerability to excitotoxic damage, oxidative stress, and inflammatory cytokines. Besides demyelinating diseases where oligoden-drocyte injury is primarily implicated, damage to them also occurs secondarily in various neuropathies. Oligoprotec-tion should, therefore, be looked into something not just as a means for protecting oligodendrocytes alone but also as a common target of protecting neurons and the neurogliovascular unit as a whole. In this review, we provide a descrip-tion on oligodendrocytes, the reasons for their vulnerability, the evolving new concepts of protecting neurovascular unit and recently neurogliovascular unit;the various diseases where oligodendrocyte injury is implicated with a brief idea on different injury mechanisms of oligodendrocytes. Finally, we present the summary of the drugs that have shown promising results in protecting oligodendrocytes or in protecting white matter as a whole in different in-vivo and in-vitro models.

<i>In Vivo</i>Sedative and Anxiolytic Activities of <i>Thunbergia erecta</i>(Acanthaceae) Leaves Activate Gamma-Aminobutyric Acid (GABA) Mediated Hyperpolarization in Swiss Albino Mice

Background: Thunbergia erecta (Acanthaceae) is the most abundant medicinal plant in different parts of Bangladesh where it is known as “nilghonta”. It has been used as traditional medicine for insomnia, depression and anxiety management. However, no scientific evidence of T. erecta belonging to neuropharmacological activity has been reported. The aim of present study was to investigate in vivo sedative and anxiolytic activities of methanol extract from the leaves of T. erecta in Swiss Albino mice. Methods: Sedative activity of METE was investigated using open field, hole cross and thiopental sodium-induced sleeping time test model whereas anxiolytic activity was screened by elevated-plus maze, light-dark box, hole-board and marble-burying test method in mice at 200 and 400 mg/kg doses. The acute toxicity study and phytochemical analysis of METE also carried out. Diazepam used as the positive control for the following behavioral pharmacology test. Results: METE exhibited significant (p Conclusion: The experimental result indicates T. erecta contains phytoconstituents that possess sedative and anxiolytic activity which traditionally used in insomnia, depression and anxiety management.

Structure-activity relationship of pyrazol-4-ylpyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor4(M4)in schizophrenia and dementia with Lewy bodies,however,a clinically validated M4positron emission tomography(PET)radioligand is currently lacking.As such,the aim of this study was to develop a suitable M4PET ligand that allows the non-invasive visualization of M4in the brain.Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12—a subtype-selective positive allosteric modulator(PAM).The radiofluorinated analogue,[18F]12,was synthesized in 28±10%radiochemical yield,>37 GBq/μmol and an excellent radiochemical purity>99%.Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of[18F]12 for the M4-rich striatum.However,in the presence of carbachol,a significant increase in tracer binding was observed in the rat striatum,which was reduced by>60%under blocking conditions,thus indicating that orthosteric ligand interaction is required for efficient binding o f[18F]12 to the allosteric site.Remarkably,however,the presence of carbachol was not required for high specific binding in the non-human primate(NHP)and human striatum,and did not further improve the specificity and selectivity of[18F]12 in higher species.These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP,where peak brain uptake of[18F]12 was found in the putamen and temporal cortex.In conclusion,we report on the identification and preclinical development of the first radiofluorinated M4PET radioligand with promising attributes.The availability of a clinically validated M4PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

Norepinephrine:the next therapeutics frontier for Parkinson’s disease

Tissue concentrations of norepinephrine(NE)are markedly decreased in various regions of the Parkinson’s disease(PD)brain.As in the substantia nigra pars compacta,neuronal dropout and Lewy bodies are prominent changes affecting the locus coeruleus,which is the source of ascending NErgic projections.Despite the major roles of NE throughout the brain,there has been only minimal exploration of pharmacological intervention with NErgic neurotransmission.Cognitive operations,“freezing”of gait,tremor,dyskinesia,REM sleep regulation,and other aspects of brain function are tied into signaling by NE,and there is also evidence that it may have a role in the neurodegenerative process itself.This article reviews the reported pharmacological experience in PD therapeutics.