Context Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D 2 receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia. Objective To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies. Data Sources The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011. Study Selection A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function. Data Extraction Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables. Data Synthesis There was a highly significant elevation (P  2/3 receptor availability (Cohen d = 0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used. Conclusions The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D 2/3 receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/1151090/yma120002_776_786.pdf

The nature of dopamine dysfunction in schizophrenia and what this means for treatment

Publisher Summary This chapter describes the role of adenosine in brain function Adenosine is an endogenous neuromodulator that influences many functions in the central nervous system (CNS) The levels of adenosine increase when there is an imbalance between the rates of energy use and the rates of energy delivery Increased neuronal activity, and hypoxia or ischemia results in elevated levels of adenosine Adenosine receptors (ARs) were based on the ability of methylxanthines, such as theophylline and caffeine to act as antagonists The two receptors, A1 and A2, inhibit and stimulate adenylyl cyclase respectively The functions of ARs include: (1) regulation of nerve activity, (2) regulation of transmitter release, (3) interaction with other transmitter systems, and (4) various other functions Increased extracellular adenosine in response to ischemia and hypoxia acts as a neuro-protectant during cerebral ischemia and other neuronal insults ARs (A 1 Rs and A 2A Rs) are expressed at moderate to high levels in the brain areas enriched with dopaminergic innervation, thus providing an anatomical basis for interaction between these neurotransmitter systems Different features of the phenotypes provide clues to the roles of defects in AR genes in human disease The chapter discusses the roles of adenosine A 2A receptors in neurodegenerative disorders and ARs in psychiatric disorders Caffeine is used to improve wakefulness and the main actions of caffeine are mediated by brain ARs Adenosine might be an endogenous regulator of sleep–wake cycles, as adenosine analogs induced a sleep-like state In addition, ARs may play many roles in pathways that contribute to pain Clearly much additional work is needed to pinpoint the sites and mechanisms of action, as well as the roles in chronic pain states

Adenosine and Brain Function

Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A1 receptors (A1Rs) and the less abundant, but widespread, facilitatory A2ARs. It is commonly assumed that A1Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A1R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A1Rs in chronic noxious situations. In contrast, A2ARs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A2AR antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A2AR antagonists as novel protective agents in neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, ischemic brain damage and epilepsy. The greater interest of A2AR blockade compared to A1R activation does not mean that A1R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A2AR antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A1Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.

/pdf/neuroprotection-by-adenosine-in-the-brain-from-a1-receptor-4blubvf8oj.pdf

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Distribution, biochemistry and function of striatal adenosine A2A receptors

Intranasal delivery: physicochemical and therapeutic aspects.

The antibacterial activity against Staphylococcus aureus of long-chain fatty alcohols was investigated, with a focus on normal alcohols. The antibacterial activity varied with the length of the aliphatic carbon chain and not with the water/octanol partition coefficient. 1-Nonanol, 1-decanol and 1-undecanol had bactericidal activity and membrane-damaging activity. 1-Dodecanol and 1-tridecanol had the highest antibacterial activity among the long-chain fatty alcohols tested, but had no membrane-damaging activity. Consequently, it appears that not only the antibacterial activity but also the mode of action of long-chain fatty alcohols might be determined by the length of the aliphatic carbon chain.

/pdf/antibacterial-activity-of-long-chain-fatty-alcohols-against-rns1ukilrc.pdf

Antibacterial activity of long-chain fatty alcohols against Staphylococcus aureus.

To develop PET ligands for mapping central nervous system (CNS) adenosine A 2a receptors that are localized in the striatum and are coupled with dopamine receptors, 3 11 C-labeled xanthine-type adenosine A 2a antagonists, [ 11 C]KF18446 ([7-methyl- 11 C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine), [ 11 C]KF19631 ([7-methyl- 11 C]-(E)-1 ,3-diallyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthine), and [ 11 C]CSC ([7-methyl- 11 C]-8-chlorostyrylcaffeine), were compared with [ 11 C]KF17837 ([7-methyl- 11 C]-(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine). Methods: The regional brain uptake of the tracers, the effect of the coinjected adenosine antagonists on the uptake, and the metabolism were studied in mice. In rats, the regional brain uptake of the tracers was visualized by ex vivo autoradiography (ARG). The A 2a receptor binding of antagonist 1 was also measured by in vitro ARG. Imaging of the monkey brain was performed with PET with antagonist 1. Results: In mice, the highest striatal uptake was found for antagonist 1 followed by antagonists 2 and 4. The uptake was inhibited by each of 3 KF compounds and by CSC, but not by an A 1 antagonist KF15372. Another selective nonxanthine-type A 2a antagonist SCH 58261 significantly decreased the striatal uptake of only antagonist 1, the labeled metabolites of which were less than 20% in the plasma 30 min postinjection, but were negligible in the brain tissue. In ex vivo ARG, antagonist 1 showed the highest striatal uptake and the highest uptake ratio of the striatum to the other brain regions. A high and selective binding of antagonist 1 to the striatum was also confirmed by in vitro ARG. PET with antagonist 1 visualized adenosine A 2a receptors in the monkey striatum. Conclusion: These results indicate that antagonist 1 ([ 11 C]KF18446) is the most suitable PET ligand for mapping adenosine A 2a receptors in the CNS.

11C-Labeled KF18446: A Potential Central Nervous System Adenosine A2a Receptor Ligand

Micellization of conjugated chenodeoxy- and ursodeoxycholates and solubilization of cholesterol into their micelles: comparison with other four conjugated bile salts species.

Kazutoyo Endo

Papers

Antibacterial activity of long-chain fatty alcohols against Staphylococcus aureus.

11C-Labeled KF18446: A Potential Central Nervous System Adenosine A2a Receptor Ligand

Micellization of conjugated chenodeoxy- and ursodeoxycholates and solubilization of cholesterol into their micelles: comparison with other four conjugated bile salts species.

Study of thermodynamic parameters for solubilization of plant sterol and stanol in bile salt micelles.

A PET-MRI registration technique for PET studies of the rat brain.