CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 15, Issue 3, 2016

Over 100 million individuals are affected by irreversible visual impairments and blindness worldwide, while ocular diseases remain a challenging problem despite significant advances in modern ophthalmology. Development of novel drugs and drug delivery mechanisms, as well as advanced ophthalmological techniques requires experimental models including animals, capable of developing ocular diseases with similar etiology and pathology, suitable for future trials of new therapeutic approaches. Although experimental ophthalmology and visual research are traditionally performed on rodent models, these animals are often unsuitable for pre-clinical drug efficacy and safety studies, as well as for testing novel drug delivery approaches, e.g. controlled release of pharmaceuticals using intra-ocular implants. Therefore, rabbit models of ocular diseases are particularly useful in this context, since rabbits can be easily handled, while sharing more common anatomical and biochemical features with humans compared to rodents, including longer life span and larger eye size. This review provides a brief description of clinical, morphological and mechanistic aspects of the most common ocular diseases (dry eye syndrome, glaucoma, age-related macular degeneration, light-induced retinopathies, cataract and uveitis) and summarizes the diversity of current strategies for their experimental modeling in rabbits. Several applications of some of these models in ocular pharmacology and eye care strategies are also discussed.

Green tea is a beverage consumed around the world that is believed to have substantial health benefits such as reducing the risk of cancer, cardiovascular diseases, diabetes and neurodegeneration. This beverage is prepared from the leaves (steamed and dried) of the Camellia sinesis plant and contains strong antioxidant and neuroprotective phenolic compounds from which the most important is (-)-Epigallocatechin-3-gallate. Parkinson’s disease (PD) is the second more common neurodegenerative disorders, after Alzheimer’s disease and is characterized by degeneration of dopaminergic neurons in the pars compact of the substantia nigra of the basal ganglia. It has been shown in pre-clinical and clinical studies that green tea may be able to prevent PD, but its optimal dose or a possible mechanism explaining its health benefit in PD has not been properly established. In this review, we discuss the potential role of green tea’s phenolic compounds and their therapeutic effectin modulating key signaling pathways in the PD brain.

Free radicals are generated as byproduct of our body metabolism, and their adverse effect on normal functioning of our body is prevented by body’s own antioxidant machinery. Any perturbation in the defense mechanism of antioxidants inside body, its abnormal production or its induction from environment to our body lead to serious threats and is responsible for the development of various neurodegenerative disorders (NDDs). Perturbed antioxidants result in sensory and functional impairments in neuronal cells, which in turn cause NDDs. Free radical attack on neuronal cells plays a catastrophic role in NDDs. Impaired metabolism and generation of excessive reactive oxygen species also lead to a range of NDDs. Free radical induced toxicity is responsible for DNA injury, protein degradation, damage to tissue inflammation and cell death. Besides various genetic and environmental factors, free radical induced oxidative stress is also a major cause of NDDs. Application of upstream and downstream antioxidant therapy to counter oxidative stress can be an effective option in alteration of any neuronal impairment besides free radical scavenging. In the present manuscript, we have presented a comprehensive update on the symptoms, causes and cures of NDDs in relation with their dynamic association with oxidative stress.

Aging is associated with a progressive loss of muscle strength and mass, and a decline in neurophysiologic functions, which are characteristic features of neuromuscular disorders (NMDs). Understanding aging induced neuromuscular junction (NMJ) dysfunction is very crucial to understand the mechanism underlying NMDs. Morphological and physiological changes result in remodelling of the motor unit and a decline in the number of motor neuron muscle fibres. These alterations lead to excitation–contraction uncoupling and a loss of communication between the neuromuscular system, causing a decline in skeletal muscle strength and muscle mass. Understanding the molecular basis of NMJ dysfunction is essential in search for new treatment options. Besides structural and molecular studies, search for animal models to establish connection between brain and muscle is needed. Among various factors it has been observed that stress is one of the leading causes of NMDs. In the present review, we aim to explore various factors linking stress and NMDs neuromuscular disorders which gets aggravated by aging, with a special emphasis on mitochondrial connection. This in turn will help us gain new insights in the treatment of NMDs by aiding in improved symptoms, increased mobility and prolonged life.

Chronic inflammation is characterized by longstanding microglial activation followed by sustained release of inflammatory mediators, which aid in enhanced nitrosative and oxidative stress. The sustained release of inflammatory mediators propels the inflammatory cycle by increased microglial activation, promoting their proliferation and thus stimulating enhanced release of inflammatory factors. Elevated levels of several cytokines and chronic neuroinflammation have been associated with many neurodegenerative disorders of central nervous system like age-related macular degeneration, Alzheimer disease, multiple sclerosis, Parkinson’s disease, Huntington’ disease, and tauopathies. This review highlights the basic mechanisms of neuroinflammation, the characteristics of neurodegenerative diseases, and the main immunologic responses in CNS neurodegenerative disorders. A comprehensive outline for the crucial role of microglia in neuroinflammation and neurodegeneration and the role of Toll-like receptor signalling in coexistence of inflammatory mechanisms and oxidative stress as major factors responsible for progression of neurodegeneration have also been presented.

Reduction in testosterone levels in men during aging is associated with cognitive decline and risk of dementia. Animal studies have shown benefits for testosterone supplementation in improving cognition and reducing Alzheimer’s disease pathology. In a randomized, placebo-controlled, crossover study of men with subjective memory complaint and low testosterone levels, we investigated whether testosterone treatment significantly improved performance on various measures of cognitive functioning. Forty-four men were administered a battery of neuropsychological tests to establish the baseline prior to being randomly divided into two groups. The first group (Group A) received 24 weeks of testosterone treatment (T treatment) followed by 4 weeks washout, and then 24 weeks of placebo (P); the second group (Group B) received the same treatments, in reverse order (Placebo, washout, and then T treatment). In group A (TèP), compared to baseline, there was a modest (1 point) but significant improvement in general cognitive functioning as measured by the Mini Mental State Examination (MMSE) following testosterone treatment. This improvement from baseline was sustained following the washout period and crossover to placebo treatment. Similar Mini Mental State Examination (MMSE) scores were observed when comparing testosterone treatment with placebo. In group B (PèT) a significant increase was observed from baseline following testosterone treatment and a trend towards an increase when compared to placebo treatment. Improvements in baseline depression scores (assessed by Geriatric Depression Scale) were observed following testosterone/placebo treatment in both groups, and no difference was observed when comparing testosterone with placebo treatment. Our findings indicate a modest improvement on global cognition with testosterone treatment. Larger clinical trials with a longer follow- up and with the inclusion of blood and brain imaging markers are now needed to conclusively determine the significance of testosterone treatment.

Objective: Cape gooseberry (Physalis peruviana L.) belongs to the Solanaceae family. Physalis has many medicinal properties however, the beneficial effect of physalis in protecting against neurotoxins has not yet been evaluated. This experimental study investigated the protective effect of physalis juice against the oxidative damage induced by carbon tetrachloride (CCl4) in the rat brain. Methods: The degrees of protection by physalis in brain tissues were evaluated by determining the brain levels of lipid peroxidation, nitric oxide, glutathione content and antioxidant enzyme activities (superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase and glutathione reductase), after CCl4) induction in the presence or absence of physalis. Adult male albino Wistar rats were divided into 4 groups, Group I served as the control group, Group II was intraperitoneally treated with 2 ml CCl4)/kg bwt for 12 weeks, Group III was supplemented with physalis juice via the drinking water for 12 weeks, Group IV was supplemented with physalis juice and was intraperitoneally injected weekly with CCl4). Results: Treatment with CCl4) was significantly associated with a disturbance in the oxidative status in the brain tissues; this was marked by a significant (p<0.05) elevation in the lipid peroxidation and nitric oxide levels with a concomitant reduction in glutathione content compared to the control, along with a remarkable reduction in antioxidant enzymes. The administration of physalis along with CCl4) juice significantly (p<0.05) alleviated the changes in enzymatic antioxidant activity when compared to the CCl4) treated group. Furthermore, physalis juice supplemention inhibited apoptosis, as indicated by the increase of Bcl-2 immunoreactivity in brain tissue. Conclusion: Our results suggest that physalis juice could be effective in preventing neurotoxicity and the neuroprotective effect of physalis might be mediated via antioxidant and anti-apoptosis activities.

Trehalose, a chemical chaperone and mTOR-independent autophagy enhancer, has shown promise in models of Huntington’s disease, Parkinson’s disease and tauopathies. In this study, two trehalase analogs, lactulose and melibiose, were examined for their potentials in spinocerebellar ataxia treatment. Using a SCA3 ATXN3/Q75-GFP cell model, we found that the ATXN3/Q75 aggregation was significantly prohibited by lactulose and melibiose because of their abilities to up-regulate autophagy. Meanwhile, lactulose and melibiose reduced reactive oxygen species production in ATXN3/Q75 cells. Both of them further inhibited the ATXN3/Q75 aggregation in neuronally differentiated SH-SY5Y cells. These findings suggest the therapeutic applications of novel trehalose analogs in polyglutamine aggregation-associated neurodegenerative diseases.

Ethanol induces oxidative stress and its exposure during early developmental age causes neuronal cell death which leads to several neurological disorders. We previously reported that vitamin C can protect against ethanol-induced apoptotic cell death in the developing rat brain. Here, we extended our study to understand the therapeutic efficacy of vitamin C against ethanol-induced oxidative stress, neuroinflammation mediated neurodegeneration in postnatal day 7 (PND7) rat. A single episode of ethanol (5g/kg) subcutaneous administration to postnatal day 7 rat significantly induced the production of reactive oxygen species (ROS), and activated both microglia and astrocytes followed by the induction of different apoptotic markers. On the other hand, due to its free radical scavenging properties, vitamin C treatment significantly reduced the production of reactive oxygen species, suppressed both activated microglia and astrocytes and reversed other changes including elevated level of Bax/Bcl-2 ratio, cytochrome c and different caspases such as caspase-9 and caspase-3 induced by ethanol in developing rat brain. Moreover, vitamin C treatment also reduced ethanol-induced activation of Poly [ADP-Ribose] Polymerase 1(PARP-1) and neurodegeneration as evident from Flouro-Jade-B and Nissl stainined neuronal cell death in PND7 rat brain. These findings suggest that vitamin C mitigated ethanol-induced oxidative stress, neuroinflammation and apoptotic neuronal loss and may be beneficial against ethanol damaging effects in brain development.