Muhammad Zahid Khan

The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system

Human trace amines (TAs) are endogenous compounds, previously almost ignored in human pathology for many reasons (difficulty of their measurement in biological fluids, unknown receptors for elusive amines), are now considered to play a significant role in synaptic transmission within the central nervous system (CNS) acting as neuromodulators. The recent discovery of a novel family of G-protein-coupled receptors (GPCRs) that includes individual members that are highly specific for TAs indicates a potential role for TAs as vertebrate neurotransmitters or neuromodulators, although the majority of these GPCRs so far have not been demonstrated to be activated by TAs. Human trace amine receptors (including TAAR1 TAAR2 TAAR5 TAAR6 TAAR8 TAAR9) are expressed in the brain and play significant physiological and neuropathological roles by activation of trace amines. We herein discuss the recent findings that provide insights into the functional roles of human trace amines (including P-Octopamine, β phenylethylamine, Tryptamine, Tyramine, Synephrine, 3-Iodothyronamine, 3-Methoxytyramine, N-Methyltyramine, N-Methylphenethylamine) in brain. Furthermore, we discuss the known functions of human trace amine receptors in brain.

A possible significant role of zinc and GPR39 zinc sensing receptor in Alzheimer disease and epilepsy

Zinc the essential trace element, plays a significant role in the brain development and in the proper brain functions at every stage of life. Misbalance of zinc (Zn(2+)) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as Alzheimers disease, Depression, and Epilepsy. In brain, Zn(2+) has been identified as a ligand, capable of activating and inhibiting the receptors including the NMDA-type glutamate receptors (NMDARs), GABAA receptors, nicotinic acetylcholine receptors (nAChRs), glycine receptors (glyR) and serotonin receptors (5-HT3). Recently GPR39 has been identified as a zinc-specific receptor, widely expressed in brain tissues including the frontal cortex, amygdala, and hippocampus. GPR39, when binding with Zn(2+) has shown promising therapeutic potentials. This review presents current knowledge regarding the role of GPR39 zinc sensing receptor in brain, with a focus on Alzheimers disease and Epilepsy. Although the results are encouraging, further research is needed to clarify zinc and GPR39 role in the treatment of Alzheimers disease and Epilepsy.

GPR40 receptor activation leads to CREB phosphorylation and improves cognitive performance in an Alzheimer's disease mouse model.

Alzheimers disease (AD) is a very complex neurodegenerative disorder as neuronal loss is a prominent and initial feature of AD. This loss correlates with cognitive deficits more closely than amyloid load. GPR40 receptor belongs to the class of G-protein coupled receptors, is expressed in wide parts of the brain including the hippocampus which is involved in spatial learning and memory. Till now, there are few studies investigating the functional role of GPR40 in brain. In this study, we evaluated the functional role of GPR40 receptor in the A-beta AD mice model. Administration of Aβ1-42 (410pmol) intracerebroventricularly (i.c.v.) once at the beginning of experiment significantly impaired cognitive performance (in step-through passive test), the ability of spatial learning and memory in (Morris water maze test), working memory, attention, anxiety in (Novel object recognition test), and spatial working and reference-memory in (Hole board discrimination test) compared with the control group. The results revealed that GPR40 receptor treatment groups significantly ameliorated model mice cognitive performance. All GPR40 receptor agonist GW9508, treatment groups enhanced the learning and memory ability in Step-through passive test, Morris water maze test, Hole board discrimination test, Novel object recognition test. Furthermore, we have observed that activation of GPR40 receptor provoked the phosphorylation of the cAMP response element binding protein (CREB) and significant increase in neurotropic factors including brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrohin-4 (NT-4) in mouse hippocampal neurons and contribute to neurogenesis. These results suggest that GPR40 is a suitable therapeutic candidate for neurogenesis and neuroprotection in the treatment and prevention of AD.

The emerging role of GPR50 receptor in brain.

GPR50 receptor one of the member of G protein-coupled receptors (GPCRs) is extensively expressed in the pituitary, hypothalamus,cortex, midbrain, pons, amygdala, and in several brainstem nuclei. The exact function of this receptor in brain is remains unclear. This review presents current knowledge regarding the function of GPR50 receptor in brain, with a focus on role of this receptor in the hypothalamus-pituitary-adrenal (HPA) axis and the glucocorticoid receptor (GR) signaling, leptin signaling, adaptive thermogenesis, torpor, neurite outgrowth, and self-renewal and neuronal differentiation of neural progenitor cells NPCs. Although the results are encouraging, further research is needed to clarify GPR50 role in neurobiology of mood disorders, adaptive thermogenesis, torpor, and in the pathophysiology of neurological disorders.

Neuro-psychopharmacological perspective of Orphan receptors of Rhodopsin (class A) family of G protein-coupled receptors

BackgroundIn the central nervous system (CNS), G protein-coupled receptors (GPCRs) are the most fruitful targets for neuropsychopharmacological drug development. Rhodopsin (class A) is the most studied class of GPCR and includes orphan receptors for which the endogenous ligand is not known or is unclear. Characterization of orphan GPCRs has proven to be challenging, and the production pace of GPCR-based drugs has been incredibly slow.ObjectiveDetermination of the functions of these receptors may provide unexpected insight into physiological and neuropathological processes. Advances in various methods and techniques to investigate orphan receptors including in situ hybridization and knockdown/knockout (KD/KO) showed extensive expression of these receptors in the mammalian brain and unmasked their physiological and neuropathological roles. Due to these rapid progress and development, orphan GPCRs are rising as a new and promising class of drug targets for neurodegenerative diseases and psychiatric disorders.ConclusionThis review presents a neuropsychopharmacological perspective of 26 orphan receptors of rhodopsin (class A) family, namely GPR3, GPR6, GPR12, GPR17, GPR26, GPR35, GPR39, GPR48, GPR49, GPR50, GPR52, GPR55, GPR61, GPR62, GPR63, GPR68, GPR75, GPR78, GPR83, GPR84, GPR85, GPR88, GPR153, GPR162, GPR171, and TAAR6. We discussed the expression of these receptors in mammalian brain and their physiological roles. Furthermore, we have briefly highlighted their roles in neurodegenerative diseases and psychiatric disorders including Alzheimer’s disease, Parkinson’s disease, neuroinflammation, inflammatory pain, bipolar and schizophrenic disorders, epilepsy, anxiety, and depression.

Risperidone ameliorated Aβ1-42-induced cognitive and hippocampal synaptic impairments in mice

HighlightsRisperidone improved the cognitive impairment of AD mice.Risperidone inhibited the generation of A&bgr; and p‐Tau.Risperidone inhibited the neurons apoptosis induced by A&bgr;1‐42. Abstract Alzheimer’s disease (AD) is a complex neurodegenerative disorder with cognitive impairment and major neuropathologic hallmark of amyloid‐beta (A&bgr;) peptides. Risperidone, an atypical antipsychotic, can improve concentration and cognitive deficit in schizophrenia patients. In this study, behavior tests including Morris Water Maze test, Step‐through passive avoidance test, Open Field test, Step‐Down test, Hole‐Board test and Novel object recognition test were preformed to examine the effect of Risperidone on A&bgr;1‐42‐induced cognitive dysfunction in both long‐term and short‐term memory. Furthermore, ELISA assay was conducted to measure the levels of A&bgr;1‐42, BACE1 and p‐Tau in the hippocampus and cortex. Moreover, primary cortical neuron was cultured in vitro, and the cell viability, mitochondrial membrane potential, and the level of p‐Akt, GSK3&bgr; and Caspase‐3 protein were measured. For behavior tests, the results showed that Risperidone significantly reversed the A&bgr;1‐42‐induced dysfunction in learning, memory, locomotor activity and exploratory behavior. As detected by ELISA assay, risperidone decreased the levels of A&bgr;1‐42, BACE1 and p‐Tau in the hippocampus and cortex of AD model mice. Biochemical assay showed that Risperidone reversed the A&bgr;1‐42‐induced decrease of cell viability and mitochondrial membrane potential in cultured cortical neurons. The expression of p‐Akt was increased, whereas the expression of GSK3&bgr; and Caspase‐3 were decreased. These results suggested that Risperidone may be used as a promising candidate for AD treatment, for its effects of inhibiting A&bgr; generation and improving cognitive impairment in mice.

Neuroprotective effects of Caralluma tuberculata on ameliorating cognitive impairment in a d-galactose-induced mouse model.

Cognitive deficiency and oxidative stress have been well documented in aging disorders including Alzheimers disease. The aim of this study was to investigate the therapeutic efficacy of Caralluma tuberculata methanolic extract (CTME) on cognitive impairment in mice induced with d-galactose. In this study we assessed the therapeutic efficacy of CTME on cognitive impairment in mice induced with d-galactose by conduction of behavioral and cognitive performance tests. In order to explore the possible role of CTME against d-galactose-induced oxidative damages, various biochemical indicators were assessed. Chronic administration of d-galactose (150mg/kgd, s.c.) for 7 weeks significantly impaired cognitive performance (in step-through passive, active avoidance test, Hole-Board test, Novel object recognition task and Morris water maze) and oxidative defense as compared to the control group. The results revealed that CTME treatment for two weeks (100, 200 and 300mg/kg p.o) significantly ameliorated cognitive performance and oxidative defense. All groups of CTME enhanced the learning and memory ability in step-through passive, active avoidance test, Hole-Board test Novel object recognition task and Morris water maze. Furthermore, high and middle level of CTME (300 and 200mg/kg p.o) significantly increased Total antioxidative capacity (T-AOC), Glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity, neprilysin (NEP), and β-site AβPP cleaving enzyme 1 (BACE1) expression while Nitric Oxide (NO), Nitric Oxide Synthase (NOS) activity and Malondialdehyde (MDA) concentration, and the level of Aβ1-42 and presenilin 1 (PS1) were decreased. The present study showed that CTME have a significant relieving effect on learning, memory and spontaneous activities in d-galactose-induced mice model, and ameliorates cognitive impairment and biochemical dysfunction in mice.

Exo-organoplasty interventions: A brief review of past, present and future directions for advance heart failure management.

Heart failure (HF) is a debilitating disease in which abnormal function of the heart leads to imbalance of blood demand to tissues and organs. The pathogenesis of HF is very complex and various factors can contribute including myocardial infarction, ischemia, hypertension and genetic cardiomyopathies. HF is the leading cause of death and its prevalence is expected to increase in parallel with the population age. Different kind of therapeutic approaches including lifestyle modification, medication and pacemakers are used for HF patients in NYHA I-III functional class. However, for advance stage HF patients (NYHA IV), ventricle assist devices are clinically use and stem cells are under active investigation. Most of these therapies leads to modest symptoms relief and have no significant role in long-term survival rate. Currently there is no effective treatment for advance HF except heart transplantation, which is still remain clinically insignificant because of donor pool limitation. As HF is a result of multiple etiologies therefore multi-functional therapeutic platform is needed. Exo-organoplasty interventions are studied from almost one century. The major goals of these interventions are to treat various kind of heart disease from outside the heart muscle without having direct contact with blood. Various kind of interventions (devices and techniques) are developed in this arena with the passage of time. The purpose of this review is to describe the theory behind intervention devices, the devices themselves, their clinical results, advantages and limitations. Furthermore, to present a future multi-functional therapeutic platform (ASD) for advance stage HF management.

Establishment of a rat model of chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) induced by immunization with a novel peptide T2

BACKGROUND The exact etiological mechanism of Chronic Prostatitis/chronic pelvic pain syndrome (CP/CPPS) is still unclear however autoimmunity is the most valid theory. We developed a rat model of Chronic Prostatitis/chronic pelvic pain syndrome by using a novel peptide (T2) isolated from TRPM8. This model might be beneficial in elucidating mechanisms involved in the pathogenesis of Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS). METHODS 40 male Sprague-Dawley rats with an average weight of 180-220g were equally distributed into five groups. The normal control group was injected with normal saline (.9% NACL), the CFA group with CFA, AL(OH)3 group was given AL(OH)3 injection, T2 group using a novel peptide T2 and T2+AL(OH)3+CFA group was injected with T2+AL(OH)3+CFA. Dosing to all rat groups were injected subcutaneously. Hematoxylin and eosin staining and Immunohistochemistry were used to investigate inflammatory cell infiltration and IL-1β in the prostate tissue respectively. ELISA technique was used to measure the serum level of CRP and TNF-α. T-test was used to analyze the results. RESULTS Maximum infiltration of inflammatory cells and the highest level of IL-1β in the prostate tissue was observed in T2+AL(OH)3+CFA group as revealed by histopathology and Immunohistochemistry, respectively. Furthermore, T2+AL(OH)3+CFA group attained the peak value of serum TNF-α and CRP as determined by ELISA technique. CONCLUSION Our results demonstrated that T2 in combination with AL(OH)3 and CFA induced severe Prostatitis in rats. We believe that our present model will be highly beneficial for investigation of the pathophysiology of Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

A novel mouse model of chronic prostatitis/chronic pelvic pain syndrome induced by immunization of special peptide fragment with aluminum hydroxide adjuvant

OBJECTIVES CP/CPPS is a commonly observed distress in male patients. Because of its little-known etiology, no effective therapy has been developed which has promising outcomes. Therefore, there is a need to develop a valid model which can mimic the etiology of CP/CPPS. MATERIALS AND METHODS Fifty male C57BL/6 mice were randomly and averagely divided into 5 groups of 10 mice each. The control group was injected with 0.9% NaCl solution. Aluminum hydroxide and T2 groups were injected with aluminum hydroxide adjuvant and T2 peptide. T2 plus complete Freund adjuvant (CFA) with aluminum hydroxide group was injected with a mixture of T2, CFA and aluminum hydroxide adjuvant. At the same time, CFA group was injected with complete Freund adjuvant. Hematoxylin-eosin stain and immunohistochemistry were used to investigate inflammatory lesion and expression of IL-β1. Furthermore, TNF-α and CRP protein levels were evaluated by using commercially available ELISA kits. The ANOVA test was used to compare the statistical differences among groups. RESULTS Prostates from a mixture of T2 plus CFA with aluminum hydroxide immunized mice showed elevated lesions and high level of inflammatory cells infiltration compared to the other groups. In addition, the levels of TNF-α, IL-β1, and CRP were also higher in the T2 plus CFA with aluminum hydroxide group as compared to the other groups. CONCLUSION Our results showed that T2 with CFA plus aluminum hydroxide adjuvant injection could successfully induce CP/CPPS in mice. This autoimmune novel model provides a useful, economic, safer, and easy tool for exploring the etiology and pathophysiology of CP/CPPS which will improve the therapeutic outcomes.