Current Neuropharmacology - Volume 17, Issue 11, 2019

Background: Nitro-oxidative stress (NOS) has been implicated in the pathophysiology of psychiatric disorders. The activity of the polymorphic antioxidant enzyme paraoxonase 1 (PON1) is altered in diseases where NOS is involved. PON1 activity may be estimated using different substrates some of which are influenced by PON1 polymorphisms. Objectives: 1) to review the association between PON1 activities and psychiatric diseases using a standardized PON1 substrate terminology in order to offer a state-of-the-art review; and 2) to review the efficacy of different strategies (nutrition, drugs, lifestyle) to enhance PON1 activities. Methods: The PubMed database was searched using the terms paraoxonase 1 and psychiatric diseases. Moreover, the database was also searched for clinical trials investigating strategies to enhance PON1 activity. Results: The studies support decreased PON1 activity as determined using phenylacetate (i.e., arylesterase or AREase) as a substrate, in depression, bipolar disorder, generalized anxiety disorder (GAD) and schizophrenia, especially in antipsychotic-free patients. PON1 activity as determined with paraoxon (i.e., POase activity) yields more controversial results, which can be explained by the lack of adjustment for the Q192R polymorphism. The few clinical trials investigating the influence of nutritional, lifestyle and drugs on PON1 activities in the general population suggest that some polyphenols, oleic acid, Mediterranean diet, no smoking, being physically active and statins may be effective strategies that increase PON1 activity. Conclusion: Lowered PON1 activities appear to be a key component in the ongoing NOS processes that accompany affective disorders, GAD and schizophrenia. Treatments increasing attenuated PON1 activity could possibly be new drug targets for treating these disorders.

Neurotrophins (NTs), particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), have attracted increasing attention in the context of visceral function for some years. Here, we examined the current literature and presented a thorough review of the subject. After initial studies linking of NGF to cystitis, it is now well-established that this neurotrophin (NT) is a key modulator of bladder pathologies, including Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) and Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS. NGF is upregulated in bladder tissue and its blockade results in major improvements on urodynamic parameters and pain. Further studies expanded showed that NGF is also an intervenient in other visceral dysfunctions such as endometriosis and Irritable Bowel Syndrome (IBS). More recently, BDNF was also shown to play an important role in the same visceral dysfunctions, suggesting that both NTs are determinant factors in visceral pathophysiological mechanisms. Manipulation of NGF and BDNF improves visceral function and reduce pain, suggesting that clinical modulation of these NTs may be important; however, much is still to be investigated before this step is taken. Another active area of research is centered on urinary NGF and BDNF. Several studies show that both NTs can be found in the urine of patients with visceral dysfunction in much higher concentration than in healthy individuals, suggesting that they could be used as potential biomarkers. However, there are still technical difficulties to be overcome, including the lack of a large multicentre placebo-controlled studies to prove the relevance of urinary NTs as clinical biomarkers.

Cocaine use disorder is manifested by repeated cycles of drug seeking and drug taking. Cocaine exposure causes synaptic transmission in the brain to exhibit persistent changes, which are poorly understood, while the pharmacotherapy of this disease has not been determined. Multiple potential mechanisms have been indicated to be involved in the etiology of cocaine use disorder. The glutamatergic system, especially N-methyl-D-aspartate (NMDA) receptors, may play a role in several physiological processes (synaptic plasticity, learning and memory) and in the pathogenesis of cocaine use disorder. The composition of the NMDA receptor subunits changes after contingent and noncontingent cocaine administration and after drug abstinence in a region-specific and timedependent manner, as well as depending on the different protocols used for cocaine administration. Changes in the expression of NMDA receptor subunits may underlie the transition from cocaine abuse to dependence, as well as the transition from cocaine dependence to cocaine withdrawal. In this paper, we summarize the current knowledge regarding neuroadaptations within NMDA receptor subunits and scaffolding proteins observed following voluntary and passive cocaine intake, as well as the effects of NMDA receptor antagonists on cocaine-induced behavioral changes during cocaine seeking and relapse.

Background: Cognitive reserve (CR) refers to the ability of an individual to cope with brain pathology remaining free of cognitive symptoms. This protective factor has been related to compensatory and more efficient brain mechanisms involved in resisting brain damage. For its part, Brain reserve (BR) refers to individual differences in the structural properties of the brain which could also make us more resilient to suffer from neurodegenerative and mental diseases. Objective: This review summarizes how this construct, mainly mediated by educational level, occupational attainment, physical and mental activity, as well as successful social relationships, has gained scientific attention in the last years with regard to diseases, such as neurodegenerative diseases, stroke or traumatic brain injury. Nevertheless, although CR has been studied in a large number of disorders, few researches have addressed the role of this concept in drug addiction. Methods: We provide a selective overview of recent literature about the role of CR and BR in preventing substance use onset. Likewise, we will also discuss how variables involved in CR (healthy leisure, social support or job-related activities, among others) could be trained and included as complementary activities of substance use disorder treatments. Results: Evidence about this topic suggests a preventive role of CR and BR on drug use onset and when drug addiction is established, these factors led to less severe addiction-related problems, as well as better treatment outcomes. Conclusion: CR and BR are variables not taken yet into account in drug addiction. However, they could give us a valuable information about people at risk, as well as patient’s prognosis.

Synapses are well known as the main structures responsible for transmitting information through the release and recognition of neurotransmitters by pre- and post-synaptic neurons. These structures are widely formed and eliminated throughout the whole lifespan via processes termed synaptogenesis and synaptic pruning, respectively. Whilst the first process is needed for ensuring proper connectivity between brain regions and also with the periphery, the second phenomenon is important for their refinement by eliminating weaker and unnecessary synapses and, at the same time, maintaining and favoring the stronger ones, thus ensuring proper synaptic transmission. It is well-known that synaptic elimination is modulated by neuronal activity. However, only recently the role of the classical complement cascade in promoting this phenomenon has been demonstrated. Specifically, microglial cells recognize activated complement component 3 (C3) bound to synapses targeted for elimination, triggering their engulfment. As this is a highly relevant process for adequate neuronal functioning, disruptions or exacerbations in synaptic pruning could lead to severe circuitry alterations that could underlie neuropathological alterations typical of neurological and neuropsychiatric disorders. In this review, we focus on discussing the possible involvement of excessive synaptic elimination in Alzheimer’s disease, as it has already been reported dendritic spine loss in post-synaptic neurons, increased association of complement proteins with its synapses and, hence, augmented microglia-mediated pruning in animal models of this disorder. In addition, we briefly discuss how this phenomenon could be related to other neurological disorders, including multiple sclerosis and schizophrenia.