Dysfunction of neuronal calcium signalling in neuroinflammation and neurodegeneration

Neurodegeneration has been increasingly recognised as the leading structural correlate of disability progression in autoimmune diseases such as multiple sclerosis. Since calcium signalling is known to regulate the development of degenerative processes in many cell types, it is believed to play significant roles in mediating neurodegeneration. Because of its function as a major juncture linking various insults and injuries associated with inflammatory attack on neuronal cell bodies and axons, it provides potential for the development of neuroprotective strategies. This is of great significance because of the lack of neuroprotective agents presently available to supplement the current array of immunomodulatory treatments. In this review, we summarise the role that various calcium channels and pumps have been shown to play in the development of neurodegeneration under inflammatory autoimmune conditions. The identification of suitable targets might also provide insights into applications in non-inflammatory neurodegenerative diseases.     

Epigenetic regulation of astrocyte function in neuroinflammation and neurodegeneration

Epigenetic mechanisms control various functions throughout the body, from cell fate determination in development to immune responses and inflammation. Neuroinflammation is one of the prime contributors to the initiation and progression of neurodegeneration in a variety of diseases, including Alzheimer's and Parkinson's diseases. Because astrocytes are the largest population of glial cells, they represent an important regulator of CNS function, both in health and disease. Only recently have studies begun to identify the epigenetic mechanisms regulating astrocyte responses in neurodegenerative diseases. These epigenetic mechanisms, along with the epigenetic marks involved in astrocyte development, could elucidate novel pathways to potentially modulate astrocyte-mediated neuroinflammation and neurotoxicity. This review examines the known epigenetic mechanisms involved in regulation of astrocyte function, from development to neurodegeneration, and links these mechanisms to potential astrocyte-specific roles in neurodegenerative disease with a focus on potential opportunities for therapeutic intervention.     

The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus

Inflammation is an integral part of the body's physiological repair mechanism, unless it remains unresolved and becomes pathological, as evident in the progressive nature of neurodegeneration. Based on studies from outside the central nervous system (CNS), it is now understood that the resolution of inflammation is an active process, which is dependent on well‐orchestrated innate and adaptive immune responses. Due to the immunologically privileged status of the CNS, such resolution mechanism has been mostly ignored. Here, we discuss resolution of neuroinflammation as a process that depends on a network of immune cells operating in a tightly regulated sequence, involving the brain's choroid plexus (CP), a unique neuro‐immunological interface, positioned to integrate signals it receives from the CNS parenchyma with signals coming from circulating immune cells, and to function as an on‐alert gate for selective recruitment of inflammation‐resolving leukocytes to the inflamed CNS parenchyma. Finally, we propose that functional dysregulation of the CP reflects a common underlying mechanism in the pathophysiology of neurodegenerative diseases, and can thus serve as a potential novel target for therapy.     

Benzodiazepine-refractory status epilepticus,neuroinflammation, and interneuron neurodegeneration after acute organophosphate intoxication

Nerve agents and some pesticides such as diisopropylfluorophosphate (DFP) cause neurotoxic manifestations that include seizures and status epilepticus (SE), which are potentially lethal and carry long-term neurological morbidity. Current antidotes for organophosphate (OP) intoxication include atropine, 2-PAM and diazepam (a benzodiazepine for treating seizures and SE). There is some evidence for partial or complete loss of diazepam anticonvulsant efficacy when given 30?min or later after exposure to an OP; this condition is known as refractory SE. Effective therapies for OP-induced SE are lacking and it is unclear why current therapies do not work. In this study, we investigated the time-dependent efficacy of diazepam in the nerve agent surrogate DFP model of OP intoxication on seizure suppression and neuroprotection in rats, following an early and late therapy. Diazepam (5?mg/kg, IM) controlled seizures when given 10?min after DFP exposure (“early”), but it was completely ineffective at 60 or 120?min (“late”) after DFP. DFP-induced neuronal injury, neuroinflammation, and neurodegeneration of principal cells and GABAergic interneurons were significantly reduced by early but not late therapy. These findings demonstrate that diazepam failed to control seizures, SE and neuronal injury when given 60?min or later after DFP exposure, confirming the benzodiazepine-refractory SE and brain damage after OP intoxication. In addition, this study indicates that degeneration of inhibitory interneurons and inflammatory glial activation are potential mechanisms underlying these morbid outcomes of OP intoxication. Therefore, novel anticonvulsant and neuroprotectant antidotes, superior to benzodiazepines, are desperately needed for controlling nerve agent-induced SE and brain injury.     

Isolated spinal cord contusion in rats induces chronic brain neuroinflammation,neurodegeneration, and cognitive impairment

Cognitive dysfunction has been reported in patients with spinal cord injury (SCI), but it has been questioned whether such changes may reflect concurrent head injury, and the issue has not been addressed mechanistically or in a well-controlled experimental model. Our recent rodent studies examining SCI-induced hyperesthesia revealed neuroinflammatory changes not only in supratentorial pain-regulatory sites, but also in other brain regions, suggesting that additional brain functions may be impacted following SCI. Here we examined effects of isolated thoracic SCI in rats on cognition, brain inflammation, and neurodegeneration. We show for the first time that SCI causes widespread microglial activation in the brain, with increased expression of markers for activated microglia/macrophages, including translocator protein and chemokine ligand 21 (C–C motif). Stereological analysis demonstrated significant neuronal loss in the cortex, thalamus, and hippocampus. SCI caused chronic impairment in spatial, retention, contextual, and fear-related emotional memory—evidenced by poor performance in the Morris water maze, novel objective recognition, and passive avoidance tests. Based on our prior work implicating cell cycle activation (CCA) in chronic neuroinflammation after SCI or traumatic brain injury, we evaluated whether CCA contributed to the observed changes. Increased expression of cell cycle-related genes and proteins was found in hippocampus and cortex after SCI. Posttraumatic brain inflammation, neuronal loss, and cognitive changes were attenuated by systemic post-injury administration of a selective cyclin-dependent kinase inhibitor. These studies demonstrate that chronic brain neurodegeneration occurs after isolated SCI, likely related to sustained microglial activation mediated by cell cycle activation.     

Excitotoxicity,neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: The role of vitamin E

Glutamate-mediated excitotoxicity, neuroinflammation, and oxidative stress are common underlying events in neurodegeneration. This pathogenic “triad” characterizes the neurobiology of epilepsy, leading to seizure-induced cell death, increased susceptibility to neuronal synchronization and network alterations. Along with other maladaptive changes, these events pave the way to spontaneous recurrent seizures and progressive degeneration of the interested brain areas.In vivo models of epilepsy are available to explore such epileptogenic mechanisms, also assessing the efficacy of chemoprevention and therapy strategies at the pre-clinical level. The kainic acid model of pharmacological excitotoxicity and epileptogenesis is one of the most investigated mimicking the chronicization profile of temporal lobe epilepsy in humans. Its pathogenic cues include inflammatory and neuronal death pathway activation, mitochondrial disturbances and lipid peroxidation of several regions of the brain, the most vulnerable being the hippocampus. The importance of neuroinflammation and lipid peroxidation as underlying molecular events of brain damage was demonstrated in this model by the possibility to counteract the related maladaptive morphological and functional changes of this organ with vitamin E, the main fat-soluble cellular antioxidant and “conditional” co-factor of enzymatic pathways involved in polyunsaturated lipid metabolism and inflammatory signaling.The present review paper provides an overview of the literature supporting the potential for a timely intervention with vitamin E therapy in clinical management of seizures and epileptogenic processes associated with excitotoxicity, neuroinflammation and lipid peroxidation, i.e. the pathogenic “triad”.     

Computational epigenetics

Epigenetic research aims to understand heritable gene regulation that is not directly encoded in the DNA sequence. Epigenetic mechanisms such as DNA methylation and histone modifications modulate the packaging of the DNA in the nucleus and thereby influence gene expression. Patterns of epigenetic information are faithfully propagated over multiple cell divisions, which makes epigenetic regulation a key mechanism for cellular differentiation and cell fate decisions. In addition, incomplete erasure of epigenetic information can lead to complex patterns of non-Mendelian inheritance. Stochastic and environment-induced epigenetic defects are known to play a major role in cancer and ageing, and they may also contribute to mental disorders and autoimmune diseases. Recent technical advances such as ChIP-on-chip and ChIP-seq have started to convert epigenetic research into a high-throughput endeavor, to which bioinformatics is expected to make significant contributions. Here, we review pioneering computational studies that have contributed to epigenetic research. In addition, we give a brief introduction into epigenetics-targeted at bioinformaticians who are new to the field-and we outline future challenges in computational epigenetics.     

Population epigenetics

Our knowledge of the mechanisms that specify and propagate epigenetic states of gene expression is expanding rapidly; however, the significance of variation in epigenetic states at the population level remains largely unexplored. Population epigenetics, emerging as an active subfield at the interface of molecular genetics, genomics, and population biology, addresses questions concerning the prevalence and importance of epigenetic variation in the natural world.     

Bridging epigenetics and metabolism

Recent research suggests that chromatin-modifying enzymes are metabolic sensors regulating gene expression. Epigenetics is linked to metabolomics in response to the cellular microenvironment. Specific metabolites involved in this sensing mechanism include S-adenosylmethionine, acetyl-CoA, alphaketoglutarate and NAD⁺. Although the core metabolic pathways involving glucose have been emphasized as the source of these metabolites, the reprogramming of pathways involving non-essential amino acids may also play an important role, especially in cancer. Examples include metabolic pathways for glutamine, serine and glycine. The coupling of these pathways to the intermediates affecting epigenetic regulation occurs by “parametabolic” mechanisms. The metabolism of proline may play a special role in this parametabolic linkage between metabolism and epigenetics. Both proline degradation and biosynthesis are robustly affected by oncogenes or suppressor genes, and they can modulate intermediates involved in epigenetic regulation. A number of mechanisms in a variety of animal species have been described by our laboratory and by others. The challenge we now face is to identify the specific chromatin-modifying enzymes involved in coupling of proline metabolism to altered reprogramming of gene expression.