After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A
2A
receptor antagonist Nourianz® ...(istradefylline) developed by Kyowa Hakko Kirin Inc., Japan, as an add-on treatment to levodopa in Parkinson’s disease (PD) with “OFF” episodes. This milestone achievement is the culmination of the decade-long clinical studies of the effects of istradefylline in more than 4000 PD patients. Istradefylline is the first non-dopaminergic drug approved by FDA for PD in the last two decades. This approval also provides some important lessons to be remembered, namely, concerning disease-specific adenosine signaling and targeting subpopulation of PD patients. Importantly, this approval paves the way to foster entirely novel therapeutic opportunities for adenosine A
2A
receptor antagonists, such as neuroprotection or reversal of mood and cognitive deficits in PD and other neuropsychiatric diseases.
Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by dopaminergic neurodegeneration, motor impairment and non-motor symptoms. Epidemiological and ...experimental investigations into potential risk factors have firmly established that dietary factor caffeine, the most-widely consumed psychoactive substance, may exerts not only neuroprotective but a motor and non-motor (cognitive) benefits in PD. These multi-benefits of caffeine in PD are supported by convergence of epidemiological and animal evidence. At least six large prospective epidemiological studies have firmly established a relationship between increased caffeine consumption and decreased risk of developing PD. In addition, animal studies have also demonstrated that caffeine confers neuroprotection against dopaminergic neurodegeneration using PD models of mitochondrial toxins (MPTP, 6-OHDA, and rotenone) and expression of α-synuclein (α-Syn). While caffeine has complex pharmacological profiles, studies with genetic knockout mice have clearly revealed that caffeine's action is largely mediated by the brain adenosine A
receptor (A
R) and confer neuroprotection by modulating neuroinflammation and excitotoxicity and mitochondrial function. Interestingly, recent studies have highlighted emerging new mechanisms including caffeine modulation of α-Syn degradation with enhanced autophagy and caffeine modulation of gut microbiota and gut-brain axis in PD models. Importantly, since the first clinical trial in 2003, United States FDA has finally approved clinical use of the A
R antagonist istradefylline for the treatment of PD with OFF-time in Sept. 2019. To realize therapeutic potential of caffeine in PD, genetic study of caffeine and risk genes in human population may identify useful pharmacogenetic markers for predicting individual responses to caffeine in PD clinical trials and thus offer a unique opportunity for "personalized medicine" in PD.
It has long been proposed that doping a chiral spin liquid (CSL) or fractional quantum Hall state can give rise to topological superconductivity. Despite intensive effort, definitive evidences still ...remain lacking. We address this problem by studying the t − J model supplemented by time-reversal symmetry breaking chiral interaction Jχon the triangular lattice using density-matrix renormalization group with a finite concentration δ of doped holes. It has been established that the undoped, i.e., δ = 0, system has a CSL ground state in the parameter region 0.32 ≤ Jχ/J ≤ 0.56. Upon light doping, we find that the ground state of the system is consistent with a Luther-Emery liquid with power-law superconducting and charge-density-wave correlations but short-range spin-spin correlations. In particular, the superconducting correlations, whose pairing symmetry is consistent with d ± id wave, are dominant at all hole doping concentrations. Our results provide direct evidences that doping the CSL on the triangular lattice can naturally give rise to topological superconductivity.
Abstract
We study the ground state properties of the Hubbard model on three-leg triangular cylinders using large-scale density-matrix renormalization group simulations. At half-filling, we identify ...an intermediate gapless spin liquid phase, which has one gapless spin mode and algebraic spin–spin correlations but exponential decay scalar chiral–chiral correlations, between a metallic phase at weak coupling and Mott insulating dimer phase at strong interaction. Upon light doping the gapless spin liquid, the system exhibits power-law charge-density-wave (CDW) correlations but short-range single-particle, spin–spin, and chiral–chiral correlations. Similar to CDW correlations, the superconducting correlations also decay in power-law but oscillate in sign as a function of distance, which is consistent with the striped pair-density wave. When further doping the gapless spin liquid phase or doping the dimer order phase, another phase takes over, which has similar CDW correlations but all other correlations decay exponentially.
Adenosine and adenosine receptors (ARs) are increasingly recognized as important therapeutic targets for controlling cognition under normal and disease conditions for its dual roles of ...neuromodulation as well as of homeostatic function in the brain. This chapter first presents the unique ability of adenosine, by acting on the inhibitory A1 and facilitating A2A receptor, to integrate dopamine, glutamate, and BNDF signaling and to modulate synaptic plasticity (e.g., long-term potentiation and long-term depression) in brain regions relevant to learning and memory, providing the molecular and cellular bases for adenosine receptor (AR) control of cognition. This led to the demonstration of AR modulation of social recognition memory, working memory, reference memory, reversal learning, goal-directed behavior/habit formation, Pavlovian fear conditioning, and effort-related behavior. Furthermore, human and animal studies support that AR activity can also, through cognitive enhancement and neuroprotection, reverse cognitive impairments in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, and schizophrenia. Lastly, epidemiological evidence indicates that regular human consumption of caffeine, the most widely used psychoactive drug and nonselective AR antagonists, is associated with the reduced cognitive decline in aging and AD patients, and with the reduced risk in developing PD. Thus, there is a convergence of the molecular studies revealing AR as molecular targets for integrating neurotransmitter signaling and controlling synaptic plasticity, with animal studies demonstrating the strong procognitive impact upon AR antagonism in normal and disease brains and with epidemiological and clinical evidences in support of caffeine and AR drugs for therapeutic modulation of cognition. Since some of adenosine A2A receptor antagonists are already in phase III clinical trials for motor benefits in PD patients with remarkable safety profiles, additional animal and human studies to better understand the mechanism underlying the AR-mediated control of cognition under normal and disease conditions will provide the required rationale to stimulate the necessary clinical investigation to rapidly translate adenosine and AR drug as a novel strategy to control memory impairment in neuropsychiatric disorders.
Nucleus accumbens (NAc) is involved in behaviors that depend on heightened wakefulness, but its impact on arousal remains unclear. Here, we demonstrate that NAc dopamine D1 receptor (D1R)-expressing ...neurons are essential for behavioral arousal. Using in vivo fiber photometry in mice, we find arousal-dependent increases in population activity of NAc D1R neurons. Optogenetic activation of NAc D1R neurons induces immediate transitions from non-rapid eye movement sleep to wakefulness, and chemogenetic stimulation prolongs arousal, with decreased food intake. Patch-clamp, tracing, immunohistochemistry, and electron microscopy reveal that NAc D1R neurons project to the midbrain and lateral hypothalamus, and might disinhibit midbrain dopamine neurons and lateral hypothalamus orexin neurons. Photoactivation of terminals in the midbrain and lateral hypothalamus is sufficient to induce wakefulness. Silencing of NAc D1R neurons suppresses arousal, with increased nest-building behaviors. Collectively, our data indicate that NAc D1R neuron circuits are essential for the induction and maintenance of wakefulness.
We study the ground state properties of the Hubbard model on a four-leg cylinder with doped hole concentration per site δ ≤ 12.5% using density-matrix renormalization group. By keeping a large number ...of states for long system sizes, we find that the nature of the ground state is remarkably sensitive to the presence of next-nearest-neighbor hopping t'. Without t' the ground state of the system corresponds to the insulating filled stripe phase with long-range charge-density-wave (CDW) order, and short-range incommensurate spin correlations appears. However, for a small negative t' a phase characterized by coexisting algebraic d-wave superconducting (SC) and algebraic CDW correlations. In addition, it shows short-range spin- and fermion correlations consistent with a canonical Luther-Emery (LE) liquid, except that the charge and spin periodicities are consistent with half-filled stripes instead of the 4kF and 2kF wave vectors that are generic for one-dimensional chains. For a small positive t' yet another phase takes over, showing similar SC and CDW correlations. However, the fermions are now characterized by a (nearly) infinite correlation length while the gapped spin system is characterized by simple staggered antiferromagnetic correlations. We will show that this is consistent with a LE liquid formed from a weakly coupled (BCS like) d-wave superconductor on the ladder where the interactions have only the effect of stabilizing a cuprate style magnetic resonance.
Task‐dependent volitional control of the selected neural activity in the cortex is critical to neuroprosthetic learning to achieve reliable and robust control of the external device. The volitional ...control of neural activity is driven by a motivational factor (volitional motivation), which directly reinforces the target neurons via real‐time biofeedback. However, in the absence of motor behaviour, how do we evaluate volitional motivation? Here, we defined the criterion (ΔF/F) of the calcium fluorescence signal in a volitionally controlled neural task, then escalated the efforts by progressively increasing the number of reaching the criterion or holding time after reaching the criterion. We devised calcium‐based progressive threshold‐crossing events (termed ‘Calcium PTE’) and calcium‐based progressive threshold‐crossing holding‐time (termed ‘Calcium PTH’) for quantitative assessment of volitional motivation in response to progressively escalating efforts. Furthermore, we used this novel neural representation of volitional motivation to explore the neural circuit and neuromodulator bases for volitional motivation. As with behavioural motivation, chemogenetic activation and pharmacological blockade of the striatopallidal pathway decreased and increased, respectively, the breakpoints of the ‘Calcium PTE’ and ‘Calcium PTH’ in response to escalating efforts. Furthermore, volitional and behavioural motivation shared similar dopamine dynamics in the nucleus accumbens in response to trial‐by‐trial escalating efforts. In general, the development of a neural representation of volitional motivation may open a new avenue for smooth and effective control of brain–machine interface tasks.
Key points
Volitional motivation is quantitatively evaluated by M1 neural activity in response to progressively escalating volitional efforts.
The striatopallidal pathway and adenosine A2A receptor modulate volitional motivation in response to escalating efforts.
Dopamine dynamics encode prediction signal for reward in response to repeated escalating efforts during motor and volitional conditioning.
Mice learn to modulate neural activity to compensate for repeated escalating efforts in volitional control.
figure legend Evaluation scheme of volitional motivation and behavioural motivation.
The adenosine A2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson’s disease (PD). The selective A2A ...receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A2A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification.
The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic ...insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.
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