Lack of Direct Effects of Neurotrophic Factors in an In Vitro Model of Neuroinflammation.

Neuroinflammation is associated with several neurological disorders including temporal lobe epilepsy. Seizures themselves can induce neuroinflammation. In an in vivo model of epilepsy, the supplementation of brain-derived neurotropic factor (BDNF) and fibroblast growth factor-2 (FGF-2) using a Herpes-based vector reduced epileptogenesis-associated neuroinflammation. The aim of this study was to test whether the attenuation of the neuroinflammation obtained in vivo with BDNF and FGF-2 was direct or secondary to other effects, for example, the reduction in the severity and frequency of spontaneous recurrent seizures. An in vitro model of neuroinflammation induced by lipopolysaccharide (LPS, 100 ng/mL) in a mouse primary mixed glial culture was used. The releases of cytokines and NO were analyzed via ELISA and Griess assay, respectively. The effects of LPS and neurotrophic factors on cell viability were determined by performing an MTT assay. BDNF and FGF-2 were tested alone and co-administered. LPS induced a significant increase in pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and NO. BDNF, FGF-2, and their co-administration did not counteract these LPS effects. Our study suggests that the anti-inflammatory effect of BDNF and FGF-2 in vivo in the epilepsy model was indirect and likely due to a reduction in seizure frequency and severity.

Lipids as biomarkers of brain disorders.

Brain is a central and pivotal organ of human body containing the highest lipids content next to adipose tissue. It works as a monitor for the whole body and needs an adequate supply of energy to maintain its physiological activities. This high demand of energy in the brain is chiefly maintained by the lipids along with its reservoirs. Thus, the lipid metabolism is also an important for the proper development and function of the brain. Being a prominent part of the brain, lipids play a vast number of physiological activities within the brain starting from the structural development, impulse conduction, insulation, neurogenesis, synaptogenesis, myelin sheath formation and finally to act as the signaling molecules. Interestingly, lipids bilayer also maintains the structural integrity for the physiological functions of protein. Thus, in light to all of these activities, lipids and its metabolism can be attributed pivotal for brain health and its activities. Decisively, the impaired/altered metabolism of lipids and its intermediates puts forward a key step in the progression of different brain ailments including neurodegenerative, neurological and neuropsychiatry disorders. Depending on their associated underlying pathways, they serve as the potential biomarkers of these disorders and are considered as necessary diagnostic tools. The present review discusses the role and level of altered lipids metabolism in brain diseases including neurodegenerative diseases, neurological diseases, and neuropsychiatric diseases. Moreover, the possible mechanisms of altered level of lipids and their metabolites have also been discussed in detail.

Role of cholesterol and sphingolipids in brain development and neurological diseases.

Brain is a vital organ of the human body which performs very important functions such as analysis, processing, coordination, and execution of electrical signals. For this purpose, it depends on a complex network of nerves which are ensheathed in lipids tailored myelin; an abundant source of lipids in the body. The nervous system is enriched with important classes of lipids; sphingolipids and cholesterol which compose the major portion of the brain particularly in the form of myelin. Both cholesterol and sphingolipids are embedded in the microdomains of membrane rafts and are functional units of the neuronal cell membrane. These molecules serve as the signaling molecules; hold important roles in the neuronal differentiation, synaptogenesis, and many others. Thus, their adequate provision and active metabolism are of crucial importance in the maintenance of physiological functions of brain and body of an individual. In the present review, we have highlighted the physiological roles of cholesterol and sphingolipids in the development of the nervous system as well as the association of their altered metabolism to neurological and neurodegenerative diseases.

Putative Roles of Plant-Derived Tannins in Neurodegenerative and Neuropsychiatry Disorders: An Updated Review.

Neurodegenerative and neuropsychiatric diseases are characterized by the structural and functional abnormalities of neurons in certain regions of the brain. These abnormalities, which can result in progressive neuronal degeneration and functional disability, are incurable to date. Although comprehensive efforts have been made to figure out effective therapies against these diseases, partial success has been achieved and complete functional recovery is still not a reality. At present, plants and plant-derived compounds are getting more attention because of a plethora of pharmacological properties, and they are proving to be a better and safer target as therapeutic interventions. This review aims to highlight the roles of tannins, 'the polyphenol phytochemicals', in tackling neurodegenerative diseases including Alzheimer's and Parkinson's diseases as well as neuropsychiatric disorders like depression. Among the multifarious pharmacological properties of tannins, anti-oxidative, anti-inflammatory, and anti-cholinesterase activities are emphasized more in terms of neuroprotection. The current review also throws light on mechanistic pathways by which various classes of tannins execute neuroprotective effects. Despite their beneficial properties, some harmful effects of tannins have also been elaborated.

Supplementation of Cannabis sativa L. leaf powder accelerates functional recovery and ameliorates haemoglobin level following an induced injury to sciatic nerve in mouse model.

Peripheral nerve injury is a common condition with a multitude of signs and symptoms. The major consequence of injury is limited physical activity. Presently, we are lacking effective therapies for PNI and it is need of the hour is to explore potential remedies for the recovery of functional loss. Here, we have investigated the role of crude Cannabis sativa L. leaf powder in promoting functions recovery, in mouse model subjected to a traumatic sciatic nerve injury. A dose of 200mg/kg of the body weight per day was administered orally from the day of nerve crush till the end of the experiment. The motor functions were evaluated by measuring sciatic functional index, muscle grip strength and muscle mass; whereas the sensory functions were assessed by hotplate test. The haematology and serum analyses were carried out to estimate the effect of treatment on the systemic index and oxidative stress. The gain of motor functions was significantly improved and was early noticed in the treated mice. Restoration of muscle mass and elevated haemoglobin level were statistically significant in the treatment group. This study indicates that Cannabis sativa L. supplementation accelerates the motor functions recovery after nerve compression injury.

Neurada procumbens promotes functions regain in a mouse model of mechanically induced sciatic nerve injury.

Peripheral nerve injury is a complex condition which results in restricted physical activity. Despite the tremendous efforts to figure out effective remedies, the complete functional retrieval is still a goal to be achieved. So, the need of hour is the exploration of potential natural compounds to recover this functional loss. Here, we have investigated the role of a local plant "Neurada procumbens" in ameliorating the functional recovery after an induced nerve compression injury in a mouse model. A dose of N. procumbens (50mg/kg of body weight) was administered orally from the day of injury to onwards. The motor functional recovery was assessed by evaluating muscle grip strength and sciatic functional index; while the sensory functions were gauged by the hotplate test. The serological parameters were carried out to analyze the effect of N. procumbens on oxidative stress level. The recovery of sensory and motor functions was significantly improved and perceived earlier in the treatment group. Moreover, the elevated antioxidant level was statistically significant in the treatment group. These results indicate that the supplementation of N. procumbens accelerates functional recovery after sciatic nerve crush injury.

Role of Plant-Derived Flavonoids and Their Mechanism in Attenuation of Alzheimer's and Parkinson's Diseases: An Update of Recent Data.

Neurodegeneration is a progressive loss of neuronal cells in certain regions of the brain. Most of the neurodegenerative disorders (NDDs) share the communal characteristic such as damage or reduction of various cell types typically including astrocytes and microglial activity. Several compounds are being trialed to treat NDDs but they possess solitary symptomatic advantages along with copious side effects. The finding of more enthralling and captivating compounds to suspend and standstill the pathology of NDDs will be considered as a hallmark of present times. Phytochemicals possess the potential to alternate the synthetic line of therapy against NDDs. The present review explores the potential efficacy of plant-derived flavonoids against most common NDDs including Alzheimer's disease (AD) and Parkinson's disease (PD). Flavonoids are biologically active phytochemicals which possess potential pharmacological effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic and anti-oxidant effects and are able to attenuate the pathology of various NDDs through down-regulating the nitric oxide (NO) production, by reducing the tumor necrosis factor-α (TNF-α), by reducing the excitotoxicity of superoxide as well as acting as tyrosine kinase (TK) and monoamine oxidase (MAO) inhibiting enzyme.

Low-dose 7,8-Dihydroxyflavone Administration After Status Epilepticus Prevents Epilepsy Development.

Temporal lobe epilepsy often manifests months or even years after an initial epileptogenic insult (e.g., stroke, trauma, status epilepticus) and, therefore, may be preventable. However, no such preventive treatment is currently available. Aim of this study was to test an antioxidant agent, 7,8-dihydroxyflavone (7,8-DHF), that is well tolerated and effective in preclinical models of many neurological disorders, as an anti-epileptogenic drug. However, 7,8-DHF also acts as a TrkB receptor agonist and, based on the literature, this effect may imply an anti- or a pro-epileptogenic effect. We found that low- (5 mg/kg), but not high-dose 7,8-DHF (10 mg/kg) can exert strong anti-epileptogenic effects in the lithium-pilocarpine model (i.e., highly significant reduction in the frequency of spontaneous seizures and in the time to first seizure after status epilepticus). The mechanism of these different dose-related effects remains to be elucidated. Nonetheless, considering its excellent safety profile and antioxidant properties, as well as its putative effects on TrkB receptors, 7,8-DHF represents an interesting template for the development of effective and well-tolerated anti-epileptogenic drugs.

The Dichotomous Role of Inflammation in the CNS: A Mitochondrial Point of View.

Innate immune response is one of our primary defenses against pathogens infection, although, if dysregulated, it represents the leading cause of chronic tissue inflammation. This dualism is even more present in the central nervous system, where neuroinflammation is both important for the activation of reparatory mechanisms and, at the same time, leads to the release of detrimental factors that induce neurons loss. Key players in modulating the neuroinflammatory response are mitochondria. Indeed, they are responsible for a variety of cell mechanisms that control tissue homeostasis, such as autophagy, apoptosis, energy production, and also inflammation. Accordingly, it is widely recognized that mitochondria exert a pivotal role in the development of neurodegenerative diseases, such as multiple sclerosis, Parkinson's and Alzheimer's diseases, as well as in acute brain damage, such in ischemic stroke and epileptic seizures. In this review, we will describe the role of mitochondria molecular signaling in regulating neuroinflammation in central nervous system (CNS) diseases, by focusing on pattern recognition receptors (PRRs) signaling, reactive oxygen species (ROS) production, and mitophagy, giving a hint on the possible therapeutic approaches targeting mitochondrial pathways involved in inflammation.

Strychnos nux-vomica L. seed preparation promotes functional recovery and attenuates oxidative stress in a mouse model of sciatic nerve crush injury.

BACKGROUND: Peripheral nerve injury is a debilitating condition that may lead to partial or complete motor, sensory and autonomic function loss and lacks effective therapy until date. Therefore, it is quite imperative to explore impending remedies for rapid and accurate functional retrieval following such conditions. Natural product-based intervention can prove effective to facilitate the process of functions regain. METHODS: Here, we investigated the effect of processed Strychnos nux-vomica seeds at a dose of 250 mg/kg body weight in a mouse model of induced Sciatic nerve lesion in promoting the recovery of the functions. A compression injury was induced in the Sciatic nerve of the right leg in the mice. Sensory function recovery was evaluated by hot-plate and formalin tests, whereas the motor function retrieval was assessed by measuring muscle grip strength, sciatic functional index, and muscle mass restoration. Oxidative stress and blood cell count were measured by biochemistry and haematological analyses. RESULTS: This study indicates that Strychnos nux-vomica seeds enhance the rate of recovery of both sensory and motor functions. It helps restore the muscle mass, attenuates total oxidant status and enhances the total anti-oxidant capacity of the biological system. Moreover, the treated animals manifested an enhanced glucose tolerance aptitude and augmented granulocyte and platelet counts. Improved oxidant control, enhanced glucose sensitivity and amended granulocyte and platelet counts are likely to contribute to the advantageous effects of Strychnos nux-vomica, and warrant further in-depth studies for deciphering possible mechanisms and identification of active constituent(s) responsible for these effects. CONCLUSION: Strychnos nux-vomica seed offers functional recovery promoting effects following a mechanical injury to the Sciatic nerve and the possible reasons behind this effect can be reduced oxidative stress and improved glycaemic control. Further and detailed investigations can unravel this mystery.

Current Status of Therapeutic Approaches against Peripheral Nerve Injuries: A Detailed Story from Injury to Recovery.

Peripheral nerve injury is a complex condition with a variety of signs and symptoms such as numbness, tingling, jabbing, throbbing, burning or sharp pain. Peripheral nerves are fragile in nature and can easily get damaged due to acute compression or trauma which may lead to the sensory and motor functions deficits and even lifelong disability. After lesion, the neuronal cell body becomes disconnected from the axon's distal portion to the injury site leading to the axonal degeneration and dismantlement of neuromuscular junctions of targeted muscles. In spite of extensive research on this aspect, complete functional recovery still remains a challenge to be resolved. This review highlights detailed pathophysiological events after an injury to a peripheral nerve and the associated factors that can either hinder or promote the regenerative machinery. In addition, it throws light on the available therapeutic strategies including supporting therapies, surgical and non-surgical interventions to ameliorate the axonal regeneration, neuronal survival, and reinnervation of peripheral targets. Despite the availability of various treatment options, we are still lacking the optimal treatments for a perfect and complete functional regain. The need for the present age is to discover or design such potent compounds that would be able to execute the complete functional retrieval. In this regard, plant-derived compounds are getting more attention and several recent reports validate their remedial effects. A plethora of plants and plant-derived phytochemicals have been suggested with curative effects against a number of diseases in general and neuronal injury in particular. They can be a ray of hope for the suffering individuals.

Foeniculum vulgare (Fennel) promotes functional recovery and ameliorates oxidative stress following a lesion to the sciatic nerve in mouse model.

Peripheral nerve injury is one of the major health concerns of the present era which can lead to the long-lasting disability and even demise. Currently, no effective and side effect free remedy exists and exploration of effective therapeutic strategies to regain functional outcome is a need of hour. In the present study, we used BALB/c mice (N = 14 age, 10-12 weeks & weight 32-34 g) that were divided into two groups: Normal chow (n = 7) and Fennel chow (n = 7) group. Here, we have explored the role of crude Foeniculum vulgare mill seeds in promoting functional recovery following a mechanical insult to the sciatic nerve by an oral administration of a crude dose of 500 mg/kg BW. The recovery of both sensory and motor functions was significantly (p > .05) accelerated in the treatment group, assessed by behavioral analyses alongside total antioxidant capacity increase. Conclusively, F. vulgare can be a potential therapeutic candidate for accelerating functional recovery after peripheral nerve injury. PRACTICAL APPLICATIONS: The outcomes of study have vital practical application both for scientists and consumers. The therapeutic role of phytochemicals on functional recovery has not been explored yet. This study will help figure out plant based regimen as booster for brain health and intervention against traumatic nerve injuries. Moreover, it may also attract the food and pharmaceutical industries to formulate cost effective therapeutic products. Likewise, it can prove instrumental for scientists for advance research on this aspect with more mechanistic targets.

Role of Plant Derived Alkaloids and Their Mechanism in Neurodegenerative Disorders.

Neurodegenerative diseases are conventionally demarcated as disorders with selective loss of neurons. Conventional as well as newer molecules have been tested but they offer just symptomatic advantages along with abundant side effects. The discovery of more compelling molecules that can halt the pathology of these diseases will be considered as a miracle of present time. Several synthetic compounds are available but they may cause several other health issues. Therefore, natural molecules from the plants and other sources are being discovered to replace available medicines. In conventional medicational therapies, several plants have been reported to bestow remedial effects. Phytochemicals from medicinal plants can provide a better and safer alternative to synthetic molecules. Many phytochemicals have been identified that cure the human body from a number of diseases. The present article reviews the potential efficacy of plant-derived alkaloids, which possess potential therapeutic effects against several NDDs including Alzheimer's disease (AD), Huntington disease (HD), Parkinson's disease (PD), Epilepsy, Schizophrenia, and stroke. Alkaloids include isoquinoline, indole, pyrroloindole, oxindole, piperidine, pyridine, aporphine, vinca, ß-carboline, methylxanthene, lycopodium, and erythrine byproducts. Alkaloids constitute positive roles in ameliorating pathophysiology of these illnesses by functioning as muscarinic and adenosine receptors agonists, anti-oxidant, anti-amyloid and MAO inhibitors, acetylcholinestrase and butyrylcholinesterase inhibitor, inhibitor of α-synuclein aggregation, dopaminergic and nicotine agonist, and NMDA antagonist.