Medicinal plants used in traditional Mayan medicine for the treatment of central nervous system disorders: An overview.

ETHNOPHARMACOLOGICAL RELEVANCE: For thousands of years, different cultural groups have used and transformed natural resources for medicinal purposes focused on psychological or neurological conditions. Some of these are recognized as central nervous system (CNS) disorders and diseases, whereas other ethnopsychiatric interpretations are explained in culture-specific terms. In traditional Mayan medicine, several herbs have been part of treatments and rituals focused on cultural and ethnomedical concepts. AIM OF REVIEW: This study aims to provide a comprehensive overview of the medicinal plants used in Mesoamerica by traditional healers and Mayan groups to CNS disorders and associate the traditional use with demonstrated pharmacological evidence to establish a solid foundation for directing future research. METHODS: A systematic search for primary sources of plant use reports for traditional CNS-related remedies of Mesoamerica were obtained from library catalogs, thesis and scientific databases (PubMed, Scopus, Google Scholar; and Science Direct), and entered in a database with data analyzed in terms of the usage frequency, use by ethnic groups, plant endemism, and pharmacological investigation. RESULTS: A total of 155 plants used for ethnopsychiatric conditions in Mesoamerica by Mayan groups were found, encompassing 127 native species. Of these, only 49 native species have reported in vitro or in vivo pharmacological analyses. The most commonly reported ethnopsychiatric conditions are related to anxiety, depression, memory loss, epilepsy, and insomnia. The extent of the scientific evidence available to understand the pharmacological application for their use against CNS disorders varied between different plant species, with the most prominent evidence shown by Annona cherimola, Justicia pectoralis, J. spicigera, Mimosa pudica, Persea americana, Petiveria alliacea, Piper amalago, Psidium guajava, Tagetes erecta and T. lucida. CONCLUSION: Available pharmacological data suggest that different plant species used in traditional Mayan medicine may target the CNS, mainly related to GABA, serotonin, acetylcholine, or neuroprotective pathways. However, more research is required, given the limited data regarding mechanism of action at the preclinical in vivo level, identification of active compounds, scarce number of clinical studies, and the dearth of peer-reviewed studies.

mTOR pathway: A potential therapeutic target for spinal cord injury.

Spinal cord injury (SCI) is the most common disabling spinal injury, and the complex pathological process can eventually lead to severe neurological dysfunction. Many studies have reported that the mammalian target of rapamycin (mTOR) signaling pathway plays an important role in synaptogenesis, neuron growth, differentiation, and survival after central nervous system injury. It is also involved in various traumatic and central nervous system diseases, including traumatic brain injury, neonatal hypoxic-ischemic brain injury, Alzheimer's disease, Parkinson's disease, and cerebral apoplexy. mTOR has also been reported to play an important regulatory role in various pathophysiological processes following SCI. Activation of mTOR signals after SCI can regulate physiological and pathological processes, such as proliferation and differentiation of neural stem cells, regeneration of nerve axons, neuroinflammation, and glial scar formation, through various pathways. Inhibition of mTOR activity has been confirmed to promote repair in SCI. At present, many studies have reported that Chinese herbal medicine can inhibit the SCI-activated mTOR pathway to improve the microenvironment and promote nerve repair after SCI. Due to the role of the mTOR pathway in SCI, it may be a potential therapeutic target for SCI. This review is focused on the pathophysiological process of SCI, characteristics of the mTOR pathway, role of the mTOR pathway in SCI, role of inhibition of mTOR on SCI, and role and significance of inhibition of mTOR by related Chinese herbal medicine inhibitors in SCI. In addition, the review discusses the deficiencies and solutions to mTOR and SCI research shortcomings. This study hopes to provide reference for mTOR and SCI research and a theoretical basis for SCI biotherapy.

Application and advantages of zebrafish model in the study of neurovascular unit.

The concept of "Neurovascular Unit" (NVU) was put forward, so that the research goal of Central Nervous System (CNS) diseases gradually transitioned from a single neuron to the structural and functional integrity of the NVU. Zebrafish has the advantages of high homology with human genes, strong reproductive capacity and visualization of neural circuits, so it has become an emerging model organism for NVU research and has been applied to a variety of CNS diseases. Based on CNKI (https://www.cnki.net/) and PubMed (https://pubmed.ncbi.nlm.nih.gov/about/) databases, the author of this article sorted out the relevant literature, analyzed the construction of a zebrafish model of various CNS diseases，and the use of diagrams showed the application of zebrafish in the NVU, revealed its relationship, which would provide new methods and references for the treatment and research of CNS diseases.

Electrical stimulation of cranial nerves in cognition and disease.

The cranial nerves are the pathways through which environmental information (sensation) is directly communicated to the brain, leading to perception, and giving rise to higher cognition. Because cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in the clinical, behavioral, and cognitive domains. Among other neuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nerve stimulation is unique in allowing axon pathway-specific engagement of brain circuits, including thalamo-cortical networks. In this review we amalgamate relevant knowledge of 1) cranial nerve anatomy and biophysics; 2) evidence of the modulatory effects of cranial nerves on cognition; 3) clinical and behavioral outcomes of cranial nerve stimulation; and 4) biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral metrics. Existing non-invasive stimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even with invasive stimulation methods, selective targeting of one nerve fiber type requires nuance since each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose onto other nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct sets of axons, thus supporting specific actions on cognition and behavior. To this end, a rubric for reproducible dose-response stimulation parameters is defined here. Given that afferent cranial nerve axons project directly to the brain, targeting structures (e.g. thalamus, cortex) that are critical nodes in higher order brain networks, potent effects on cognition are plausible. We propose an intervention design framework based on driving cranial nerve pathways in targeted brain circuits, which are in turn linked to specific higher cognitive processes. State-of-the-art current flow models that are used to explain and design cranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy; skull foramina and superficial tissue layers; and precise nerve morphology. Detailed simulations also predict that some non-invasive electrical or magnetic stimulation approaches that do not intend to modulate cranial nerves per se, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), may also modulate activity of specific cranial nerves. Much prior cranial nerve stimulation work was conceptually limited to the production of sensory perception, with individual titration of intensity based on the level of perception and tolerability. However, disregarding sensory emulation allows consideration of temporal stimulation patterns (axon recruitment) that modulate the tone of cortical networks independent of sensory cortices, without necessarily titrating perception. For example, leveraging the role of the thalamus as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state. We show that properly parameterized computational models at multiple scales are needed to rationally optimize neuromodulation that target sets of cranial nerves, determining which and how specific brain circuitries are modulated, which can in turn influence cognition in a designed manner.

Emerging role of nanomedicine in the treatment of neuropathic pain.

Neuropathic pain (NeP) is a complex chronic pain condition associated with nerve injury. Approximately, 7-10% of the general population across the globe is suffering from this traumatic condition, but the existing treatment strategies are inadequate to deliver pain relief and are associated with severe adverse effects. To overcome these limitations, lot of research is focussed on developing new molecules with high potency and fewer side effects, novel cell and gene-based therapies and modification of the previously approved drugs by different formulation aspects. Nanomedicine has attracted a lot of attention in the treatment of many diverse pathological conditions because of their unique physiochemical and biological properties. In this manuscript, we highlighted the emerging role of nanomedicine in different therapies (drug, cell and gene), also we emphasised on the challenges associated with nanomedicine such as development of well-characterised nanoformulation, scaling of batches with reproducible results and toxicity along with this we discussed about the future of nanomedicine in the treatment of neuropathic pain.

Uncaria rhynchophylla and its Major Constituents on Central Nervous System: A Review on Their Pharmacological Actions.

BACKGROUND: Uncaria rhynchophylla (Miq.) Jacks (Rubinaceae), a common herbal medicine known as Gou-teng in Chinese, is commonly used in Chinese medicine practice for the treatment of convulsions, hypertension, epilepsy, eclampsia and other cerebral diseases. The major active components of U. rhynchophylla are alkaloids, terpenoids and flavonoids. The protective effects of U. rhynchophylla and its major components on central nervous system (CNS) have become a focus of research in recent decades. OBJECTIVE: The study aimed to systematically summarize the pharmacological activities of U. rhynchophylla and its major components on the CNS. METHODS: This review summarized the experimental findings from our laboratories, together with other literature data obtained through a comprehensive search of databases including the Pubmed and the Web of Science. RESULTS: U. rhynchophylla and its major components such as rhynchophylline and isorhynchophylline have been shown to have neuroprotective effects on Alzheimer's disease, Parkinson's disease, depression, cerebral ischaemia through a number of mechanisms including anti-oxidant, anti-inflammatory actions and regulation on neurotransmitters. CONCLUSION: U. rhynchophylla and its major components have multiple beneficial pharmacological effects on CNS. Further studies on U. rhynchophylla and its major components are warranted to fully illustrate the underlying molecular mechanisms, pharmacokinetics, and toxicological profiles of these naturally occurring compounds and their potential for clinical application.

Melatonin, a calpain inhibitor in the central nervous system: Current status and future perspectives.

Dysregulation of neuronal Ca2+ and oxidative stress plays an important role in the activation of cysteine proteases including calpains and caspases that contribute to neuronal death. In neurodegenerative diseases, traumatic brain injury, stroke, and neuropathic pain calpain activities are markedly increased. Melatonin is a beneficial supplement in the treatment of central nervous system (CNS) disorders. Melatonin is a potent antioxidant and works as a free-radical scavenger to regulate a large number of molecular pathways, including oxidative stress, inflammation, apoptosis, and cell death under different pathological conditions. However, limited studies have evaluated the inhibitory effect of melatonin on calpains. This review summarizes the current knowledge related to the effects of melatonin on calpains in some of the common CNS disorders.

The effects of Chinese medicines on cAMP/PKA signaling in central nervous system dysfunction.

Neuropathological injury in the mammalian adult central nervous system (CNS) may cause axon disruption, neuronal death and lasting neurological deficits. Failure of axon regeneration is one of the major challenges for CNS functional recovery. Recently, the cAMP/PKA signaling pathway has been proven to be a critical regulator for neuronal regeneration, neuroplasticity, learning and memory. Also, previous studies have shown the effects of Chinese medicines on the prevention and treatment of CNS dysfunction mediated in part by cAMP/PKA signaling. In this review, the authors discuss current knowledge of the role of cAMP/PKA signaling pathway in neuronal regeneration and provide an overview of the Chinese medicines that may enable CNS functional recovery via this signaling pathway.

[The evaluation of the effectiveness of electrophoresis in the form of Polymineral wipes on the basis of iodine- bromine natural water in the young children suffering from the consequences of perinatal lesions in the central nervous system].

UNLABELLED: The background: the increased frequency of serious consequences of perinatal lesions in the central nervous system of the young children dictates the necessity to develop the effective methods of physiotherapy for the early-stage rehabilitation of such patients on the basis of an objective assessment of the adaptive reserves of the organism. MATERIAL AND METHODS: The present study involved 53 children at the age from 1 to 12 months presenting with the consequences of perinatal lesions to the central nervous system. Thirty of the children were treated with the use of electrophoresis in the form of Polymineral wipes on the basis of natural iodine-bromine water. The group of comparison was comprised of 23 children treated without physiotherapy. We estimated the clinical effectiveness and the level of adaptive resources based on the results of blood count measurements (the type of non-specific adaptive reaction and the reactivity level); in addition, the electro-acupuncture test was carried out with the use of the hardware-software complex for bioresonance (MOR) therapy. RESULTS: The clinical effectiveness of an electrophoresis in the form of Polymineral wipes on the basis of natural iodine-bromine water used for the treatment of the newborn infants with the consequences of perinatal lesions to the central nervous system amounted to 93.3%. The rearrangement of the adaptive reactions was apparent as the increase in the proportion of the antistress reactions from 63.3% to 86.7%, the decrease in the frequency of the reactivation reaction by a factor of 3.7, and the reduction of the reactivity level by a factor of 3.0. The repeated study with the use of the MORA-test revealed normalization of the altered indicators in all the children with the initially reduced or enhanced values of these indicators. In the comparison group, dynamics of clinical symptoms was less apparent, and the assessment of the adaptative resources revealed their decrease in 78.3% of the cases. CONCLUSION: The present study confirmed the beneficial effect of electrophoresis in the form of Polymineral wipes on the basis of natural iodine-bromine natural water on the dynamics of clinical symptoms and adaptive reserves in the infants suffering from the consequences of perinatal lesions to the central nervous system. The determination of the type of the nonspecific adaptive reaction and the level of reactivity in combination with the MORA-test can be a method for the assessment of the effectiveness and adequacy of physiotherapeutic modalities for the young children.

The role of zinc in the pathogenesis and treatment of central nervous system (CNS) diseases. Implications of zinc homeostasis for proper CNS function.

Zinc, the essential trace element, is known to play multiple biological functions in human organism. This metal is a component of many structural as well as regulatory and catalytic proteins. The precise regulation of zinc homeostasis is essential for central nervous system and for the whole organism. Zinc plays a significant role in the brain development and in the proper brain function at every stage of life. This article is a review of knowledge about the role of zinc in central nervous system (CNS) function. The influence of this biometal on etiopathogenesis, prevention and treatment of selected brain diseases and disorders was discussed. Zinc imbalance can result not only from insufficient dietary intake, but also from impaired activity of zinc transport proteins and zinc dependent regulation of metabolic pathways. It is known that some neurodegenerative processes are connected with zinc dyshomeostasis and it may influence the state of Alzheimer's disease, depression and ageing-connected loss of cognitive function. The exact role of zinc and zinc-binding proteins in CNS pathogenesis processes is being under intensive investigation. The appropriate zinc supplementation in brain diseases may help in the prevention as well as in the proper treatment of several brain dysfunctions.

Kainate receptors in health and disease.

Our understanding of the molecular properties of kainate receptors and their involvement in synaptic physiology has progressed significantly over the last 30 years. A plethora of studies indicate that kainate receptors are important mediators of the pre- and postsynaptic actions of glutamate, although the mechanisms underlying such effects are still often a topic for discussion. Three clear fields related to their behavior have emerged: there are a number of interacting proteins that pace the properties of kainate receptors; their activity is unconventional since they can also signal through G proteins, behaving like metabotropic receptors; they seem to be linked to some devastating brain diseases. Despite the significant progress in their importance in brain function, kainate receptors remain somewhat puzzling. Here we examine discoveries linking these receptors to physiology and their probable implications in disease, in particular mood disorders, and propose some ideas to obtain a deeper understanding of these intriguing proteins.

Índice elevado de ácidos grasos omega 6/omega 3 en niños con neuropatías causa o efecto / High ratio of omega 6/omega 3 ratio children with neuropathies cause or effect

Introducción: Los ácidos grasos n-3 y n-6 compiten por las mismas elongasas y desaturasas, siendo muy deficiente la síntesis de ácidos grasos poliinsaturados n-3 a partir de ácido linolénico. Los poliinsaturados n-3 previenen enfermedades y son importantes en el desarrollo y mantenimiento de las actividades neuronales, siendo necesaria una relación adecuada con sus antagonistas n-6. En este trabajo se estudia la proporción de estos ácidos grasos. Material y métodos: Se han analizado los ácidos grasos n-3 y n-6 en sueros y fosfolípidos de membrana de 374 niños con neuropatías y de 34 niños sanos, mediante cromatografía de gases con detector de masas. Se ha realizado el estudio estadístico pertinente. Resultados: Los ácidos grasos n-3 (EPA y DHA) en suero y su correspondientes fosfolípidos de membrana correlacionan mejor que los de la familia n-6. Los mayoritarios n-6 (LA y ARA) están en igual proporción en sueros, siendo más elevados significativamente en los fosfolípidos de los niños sanos. Los n-3 (EPA y DHA) tienen valores más altos en los niños sanos, tanto en suero como en fosfolípidos, su suma se iguala en los fosfolípidos de membrana. El índice n-6/n-3 es mayor en los niños con trastorno neurológico en ambas muestras. Conclusión: No siendo la causa de la neuropatía el alto índice n-6/n-3, sin embargo es aconsejable incrementar la ingesta de n-3, sobre todo DHA en toda la población y en especial en los niños con trastornos neurológicos (AU)

Introduction: The n-3 and n-6 fatty acids compete for the same elongases and desaturases, still highly deficient synthesis of polyunsaturated fatty acids from n-3 linolenic acid. The n-3 polyunsaturated prevent disease and are important in the development and maintenance of neuronal activities, necessitating a proper relationship with their antagonists n-6. This paper studies the proportion of these fatty acids. Material and methods: We analyzed the fatty acids of n-3 and n-6 in sera and membrane phospholipid with 374 children neuropathies and 34 healthy children, using gas chromatography with mass detector. It has made the relevant statistical study. Results: The n-3 (EPA and DHA) in serum and their corresponding membrane phospholipids correlate better than the n-6 family. The major n-6 (LA and ARA) are equally in serum, being significantly higher in phospholipids of healthy children. The n-3 (EPA and DHA) have higher values in healthy children, both in serum and phospholipids, their sum is equal to the membrane phospholipids. The n-6/n-3 ratio is higher in children with neurological disorder in both samples. Conclusion: Not being the cause of the high rate n-6/n-3 neuropathy, however it is advisable to increase the intake of n-3, DHA particularly across the population, especially in children with neurological disorders (AU)

Neuropharmacological properties of Trichosanthes dioica root.

AIM: Trichosanthes dioica Roxb. (Cucurbitaceae), commonly known as pointed gourd in English, is a dioecious climber grown widely in the Indian subcontinent. Traditionally, this plant has been used in India for several medicinal purposes. The present study aimed to evaluate certain neuropharmacological properties of the hydroalcoholic extract of T. dioica root (TDA) in experimental animal models. METHODS: TDA (at 100 and 200 mg·kg(-1) body weight, p.o.) was evaluated for anti-nociceptive activity by the acetic acid-induced writhing and tail flick methods. Locomotor depressant activity was measured by means of an actophotometer. Skeletal muscle relaxant effects were evaluated by using a rota-rod apparatus, and the sedative potentiating property by a phenobarbitone-induced sleep potentiation study. RESULTS: The results of the present study revealed significant (P < 0.001) and dose dependent anti-nociceptive, locomotor depressant, muscle relaxant, and sedative potentiating effects of TDA, demonstrating its depressant action on the central nervous system (CNS). CONCLUSION: From the present study, it can be concluded that T. dioica root possessed prominent anti-nociceptive, as well as depressant, action on the CNS, as manifested by these important neuropharmacological properties in mice.

Neurofeedback: an emerging technology for treating central nervous system dysregulation.

Neurofeedback is a machine-mediated noninvasive treatment modality based on the analysis and "feeding back" of electroencephalogram brainwaves, which has shown efficacy with a variety of central nervous system-based problems. It has special application where patients have adverse reaction to psychopharmacologic treatments and psychotherapy, cognitive behavioral therapy, and dialectical behavior therapy have proved ineffective. Treatment modalities include active forms based on operant conditioning, involving a subject's response to stimuli. Neurofeedback is strong in clinical confirmations of efficacy (case studies) and has thus far limited controlled studies in the peer-reviewed journals.

Respiratory muscle strength and training in stroke and neurology: a systematic review.

We undertook two systematic reviews to determine the levels of respiratory muscle weakness and effects of respiratory muscle training in stroke patients. Two systematic reviews were conducted in June 2011 using a number of electronic databases. Review 1 compared respiratory muscle strength in stroke and healthy controls. Review 2 was expanded to include randomized controlled trials assessing the effects of respiratory muscle training on stroke and other neurological conditions. The primary outcomes of interest were maximum inspiratory and expiratory mouth pressure (maximum inspiratory pressure and maximum expiratory pressure, respectively). Meta-analysis of four studies revealed that the maximum inspiratory pressure and maximum expiratory pressure were significantly lower (P < 0·00001) in stroke patients compared with healthy individuals (weighted mean difference -41·39 and -54·62 cmH(2) O, respectively). Nine randomized controlled trials indicate a significantly (P = 0·0009) greater effect of respiratory muscle training on maximum inspiratory pressure in neurological patients compared with control subjects (weighted mean difference 6·94 cmH(2) O) while no effect on maximum expiratory pressure. Respiratory muscle strength appears to be impaired after stroke, possibly contributing to increased incidence of chest infection. Respiratory muscle training can improve inspiratory but not expiratory muscle strength in neurological conditions, although the paucity of studies in the area and considerable variability between them is a limiting factor. Respiratory muscle training may improve respiratory muscle function in neurological conditions, but its clinical benefit remains unknown.

A narrative review on haptic devices: relating the physiology and psychophysical properties of the hand to devices for rehabilitation in central nervous system disorders.

PURPOSE: This article provides rehabilitation professionals and engineers with a theoretical and pragmatic rationale for the inclusion of haptic feedback in the rehabilitation of central nervous system disorders affecting the hand. METHOD: A narrative review of haptic devices used in sensorimotor hand rehabilitation was undertaken. Presented papers were selected to outline and clarify the underlying somatosensory mechanisms underpinning these technologies and provide exemplars of the evidence to date. RESULTS: Haptic devices provide kinaesthetic and/or tactile stimulation. Kinaesthetic haptics are beginning to be incorporated in central nervous system rehabilitation; however, there has been limited development of tactile haptics. Clinical research in haptic rehabilitation of the hand is embryonic but initial findings indicate potential clinical benefit. CONCLUSIONS: Haptic rehabilitation offers the potential to advance sensorimotor hand rehabilitation but both scientific and pragmatic developments are needed to ensure that its potential is realized.

Kynurenines in the CNS: recent advances and new questions.

Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntington's disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value.

Hypothalamo-pituitary sarcoidosis: a multicenter study of 24 patients.

AIM: To assess clinical features, treatment and outcome of Hypothalamo-pituitary (HP) sarcoidosis and to determine whether HP is associated with a particular clinical phenotype of sarcoidosis. DESIGN: Multicentric retrospective study. METHODS: Retrospective chart review. Each patient was matched with two controls. RESULTS: Twenty-four patients were identified (10 women, 14 men). Their median age at the sarcoidosis diagnosis was 31.5 years (range: 8-69 years). HP involvement occurred in the course of a previously known sarcoidosis in 11 cases (46%), whereas it preceded the diagnosis in 13 patients (54%). All but two patients had anterior pituitary dysfunction, 12 patients presented with diabetes insipidus. The most common hormonal features were gonadotropin deficiency (n=21), TSH deficiency (n=15) and hyperprolactinemia (n=12). Magnetic Resonance Imaging (MRI) revealed infundibulum involvement (n=8), pituitary stalk thickness (n=12) and involvement of the pituitary gland (n=14). All but two patients received prednisone. After a mean follow-up of 4 years, only two patients recovered from hormonal deficiencies. MRI abnormalities improved or disappeared in 12 cases under corticosteroid. There was no correlation between the hormonal dysfunctions and the radiologic outcomes. Patients with HP sarcoidosis had significantly more frequent sinonasal localizations and neurosarcoidosis and required a systemic treatment more frequently than controls. CONCLUSION: Although HP sarcoidosis is unusual, physicians should be aware that such specific localization could be the first manifestation of sarcoidosis. HP involvement is associated with general severity of sarcoidosis. MRI abnormalities can improve or disappear under corticosteroid treatment, but most endocrine defects are irreversible.

Recent advances in the drug discovery of metabotropic glutamate receptor 4 (mGluR4) activators for the treatment of CNS and non-CNS disorders.

INTRODUCTION: The metabotropic glutamate receptor type 4 (mGluR4) plays a pivotal role in a plethora of therapeutic areas, as recently demonstrated in preclinical validation studies with several chemical classes of compounds in rodent models of central nervous system (CNS) and peripheral disorders. Activation of mGluR4 with orthosteric agonists, allosteric agonists or pure positive allosteric modulators (PAM) has been postulated to be of broad therapeutic use. AREAS COVERED: The authors address past and current drug discovery efforts, insights and achievements in the field toward the identification of therapeutically promising and emerging class of mGluR4 activators, over the 2005 - 2011 period. Chemical structures, properties and in vivo pharmacological results discussed in the present review were retrieved from public literature including PubMed searches, Thomson Pharma and SciFinder databases searches, conferences, proceedings and posters. EXPERT OPINION: Developing a subtype-selective, orally bioavailable brain penetrant mGluR4 orthosteric agonist remains challenging. Lack of subtype selectivity and low brain penetration has been a common limitation of the first generation of mGluR4 agonist and potentiators. However, significant progress has recently been made with the identification of several double- to single-digit nanomolar mGluR4 PAM having reasonable pharmacokinetic properties, oral bioavailability and brain penetration. The use of such compounds in research has led to advancement in understanding the central role of mGluR4 in multiple neurodegenerative and neuroinflammatory disorders, such as Parkinson's disease and multiple sclerosis. Our understanding of the potential application of mGluR4 as therapeutic target is expected to grow as these compounds advance into preclinical and clinical development.