The molecular interplay between endocannabinoid and neurotrophin signals in the nervous system and beyond.

Neurotrophins are traditionally known for their roles in neuronal development, function and survival. More recent data has highlighted the importance of neurotrophin signalling in adult signalling contexts, including the regulation of synaptic transmission. In addition, neurotrophin levels are increased in inflammatory and neuropathic pain leading to sensitization to painful stimuli. Endocannabinoid (eCB) signalling was initially studied in the context of synaptic transmission and pain alleviation whilst recently gaining attention due to its involvement in the development of the nervous system. Similar to neurotrophins, eCB levels also rise during pain perception but result in diminished pain sensations. The overlap of cellular functions between neurotrophins and eCB signalling leads to the hypothesis that these signalling systems are positioned to regulate each other and narrow the multitude of actions that both systems can promote to the specific need of the cell. Therefore, in this review, we examine to what extent the involvement of these two signalling systems is co-ordinated as opposed to being coincidental, and causal to neuronal circuit modifications in pain. Available data point to numerous direct molecular interactions between the neurotrophin and eCB signalling systems in developmental and adult contexts, including receptor-level interplay, transcriptional control and synergistic regulation of downstream signalling cascades. Although experimental observations specifically in pain circuits are limited, the universality of downstream signalling systems from both neurotrophin and endocannabinoid receptors suggest an interdependent relationship between these two diverse signalling systems.

Ubiquitous Neural Cell Adhesion Molecule (NCAM): Potential Mechanism and Valorisation in Cancer Pathophysiology, Drug Targeting and Molecular Transductions.

Neural cell adhesion molecule, an integrated molecule of immunoglobulin protein superfamily involved in cell-cell adhesion, undergoes various structural modifications through numerous temporal-spatial regulations that generously alter their expressions on cell surfaces. These varied expression patterns are mostly envisioned in the morphogenesis and innervations of different human organs and systems. The considerable role of NCAM in neurite growth, brain development and etc. and its altered expression of NCAM in proliferating tumour cells and metastasis of various human melanomas clearly substantiate its appropriateness as a cell surface marker for diagnosis and potential target for several therapeutic moieties. This characteristic behaviour of NCAM is confined to its novel biochemistry, structural properties, signalling interactions and polysialylation. In particular, the characteristic expressions of NCAM are mainly attributed by its polysialylation, a post-translational modification that attaches polysialyl groups to the NCAM. The altered expression of NCAM on cell surface develops curiosity amidst pharmaceutical scientists, which drives them to understand its role of such expressions in various human melanomas and to elucidate the promising therapeutic strategies that are currently available to target NCAM appositely. Therefore, this review article is articulated with an insight on the altered expressions of NCAM, the clinical significances and the consequences of such atypical expression patterns in various human organs and systems.

Hypertension, Diabetes and Neurodegenerative Diseases: Is there a Clinical Link through the Ca2+/cAMP Signalling Interaction?

BACKGROUND: Hypertension, diabetes and neurodegenerative diseases are among the most prevalent medical problems around the world, costing millions of dollars to the medical health systems. Indeed, hypertension has been associated with higher risk for decline of cognition, as evidenced in patients with Alzheimer´s disease (AD). Furthermore, there is a clear relationship between hypertension and diabetes, reflecting substantial overlap in their etiology. Calcium (Ca2+) channel blockers (CCBs) have been classically prescribed for treating hypertension because of their mechanism of action due to reducing the influx of Ca2+ into the smooth muscles cells. In addition, many clinical and experimental studies have been demonstrating pleiotropic effects for CCBs. For instance, in hypertensive patients treated with CCBs, it can be observed lower incidence of neurodegenerative diseases such as AD. The virtual mechanism of action could be attributed to a restoration and maintenance of Ca2+ homeostasis, which is dysregulated in the neurodegenerative diseases, including also a reduction of neuronal apoptosis as part of these CCBs pleiotropic effects. Similarly, in hypertensive patients treated with CCBs, it can be observed an improvement of diabetes status such as glycemic control. A possible mechanism of action under debate could be attributed to a restoration of insulin secretion, then achieving glycemic control, and reduction of pancreatic ß-cell apoptosis. CONCLUSION: Considering the discovery of our group entitled "calcium paradox" due to Ca2+/cAMP signalling interaction, in this review I discussed the virtual involvement of this interaction in the pleiotropic effects of CCBs, including the possible role of the Ca2+/cAMP signalling interaction in the association between hypertension and higher risk for the decline of cognition, and diabetes.

Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca(2+)/cAMP intracellular signalling interaction.

In 2013, we discovered that the entitled "calcium paradox" phenomenon, which means a paradoxical sympathetic hyperactivity produced by l-type Ca(2+) channel blockers (CCBs), used in antihypertensive therapy, is due to interaction between the intracellular signalling pathways mediated by Ca(2+) and cAMP (Ca(2+)/cAMP interaction). In 2015, we proposed that the pharmacological manipulation of this interaction could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases. Besides the paradoxical sympathetic hyperactivity produced by CCBs, several clinical studies have been demonstrating pleiotropic effects of CCBs, including neuroprotective effects. CCBs genuinely exhibit cognitive-enhancing abilities and reduce the risk of dementia, including Alzheimer's, Parkinson´s disease and others. The molecular mechanisms involved in these pleiotropic effects remain under debate. Our recent discovery that the "calcium paradox" phenomenon is due to Ca(2+)/cAMP interaction may provide new insights for the pharmacological treatment of neurological and psychiatric disorders, including enhancement of current therapies mainly by reducing adverse effects, and improving effectiveness of modern medicines. Whether Ca(2+)/cAMP interaction is involved in CCBs pleiotropic effects also deserves special attention. Then, the pharmacological manipulation of the Ca(2+)/cAMP interaction could be a more efficient therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases. Thus, in this review we summarize the current knowledge of this field, making new directions and future perspectives.