Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. A numerous of cellular processes including oxidative stress, mitochondrial dysfunction, and accumulation of α-synuclein aggregates are considered to contribute to the pathogenesis of Parkinson's disease. A further understanding of the cellular and molecular mechanisms involved in the pathophysiology of PD is crucial for developing effective diagnostic, preventative, and therapeutic strategies to cure this devastating disorder. Preconditioning (PC) is assumed as a natural adaptive process whereby a subthreshold stimulus can promote protection against a subsequent lethal stimulus in the brain as well as in other tissues that affords robust brain tolerance facing neurodegenerative insults. Multiple lines of evidence have demonstrated that preconditioning as a possible neuroprotective technique may reduce the neural deficits associated with neurodegenerative diseases such as PD. Throughout the last few decades, a lot of efforts have been made to discover the molecular determinants involved in preconditioning-induced protective responses; although, the accurate mechanisms underlying this "tolerance" phenomenon are not fully understood in PD. In this review, we will summarize pathophysiology and current therapeutic approaches in PD and discuss about preconditioning in PD as a potential neuroprotective strategy. Also the role of gene reprogramming and mitochondrial biogenesis involved in the preconditioning-mediated neuroprotective events will be highlighted. Preconditioning may represent a promising therapeutic weapon to combat neurodegeneration.
There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS). A total of 60 male Sprague Dawley rats were randomly assigned to five groups: control, vehicle (single and chronic), and LPS PC (single and chronic). We first recorded the data regarding the behavioral and histological changes. We further investigated the alterations of gene and protein expression of important mediators in relation to TLR4 and inflammatory signaling pathways. Interestingly, significant increased presence of NFκB inhibitors [Src homology 2-containing inositol phosphatase-1 (SHIP1) and Toll interacting protein (TOLLIP)] was observed in LPS-preconditioned animals. This result was also associated with over-expression of IRF3 activity and anti-inflammatory markers, along with down-regulation of pro-inflammatory mediators. Summarizing, the analysis revealed that PC with LPS prior to seizure induction may have a neuroprotective effect possibly by reprogramming the signaling response to injury.
N-methyl-D-aspartate receptors (NMDAR) play a central role in epileptogensis and NMDAR antagonists have been shown to have antiepileptic effects in animals and humans. Despite significant progress in the development of antiepileptic therapies over the previous 3 decades, a need still exists for novel therapies. We screened an in-house library of small molecules targeting the NMDA receptor. A novel indolyl compound, 2-(1,1-Dimethyl-1,3-dihydro-benzo[e]indol-2-ylidene)-malonaldehyde, (DDBM) showed the best binding with the NMDA receptor and computational docking data showed that DDBM antagonised the binding sites of the NMDA receptor at lower docking energies compared to other molecules. Using a rat electroconvulsive shock (ECS) model of epilepsy we showed that DDBM decreased seizure duration and improved the histological outcomes. Our data show for the first time that indolyls like DDBM have robust anticonvulsive activity and have the potential to be developed as novel anticonvulsants.
Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system (CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological-based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain (ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases.
In this paper we report the differentiating properties of platelet-rich plasma releasates (PRPr) on human chondrocytes within elastomeric polycaprolactone triol-citrate (PCLT-CA) porous scaffold. Human-derived chondrocyte cellular content of glycosaminoglycans (GAGs) and total collagen were determined after seeding into PCLT-CA scaffold enriched with PRPr cells. Immunostaining and real time PCR was applied to evaluate the expression levels of chondrogenic and extracellular gene markers. Seeding of chondrocytes into PCLT-CA scaffold enriched with PRPr showed significant increase in total collagen and GAGs production compared with chondrocytes grown within control scaffold without PRPr cells. The mRNA levels of collagen II and SOX9 increased significantly while the upregulation in Cartilage Oligomeric Matrix Protein (COMP) expression was statistically insignificant. We also report the reduction of the expression levels of collagen I and III in chondrocytes as a consequence of proximity to PRPr cells within the scaffold. Interestingly, the pre-loading of PRPr caused an increase of expression levels of following extracellular matrix (ECM) proteins: fibronectin, laminin and integrin β over the period of 3 days. Overall, our results introduce the PCLT-CA elastomeric scaffold as a new system for cartilage tissue engineering. The method of PRPr cells loading prior to chondrocyte culture could be considered as a potential environment for cartilage tissue engineering as the differentiation and ECM formation is enhanced significantly.
Epilepsy is the most common and chronic neurological disorder characterized by recurrent unprovoked seizures. The key aim in treating patients with epilepsy is the suppression of seizures. An understanding of focal changes that are involved in epileptogenesis may therefore provide novel approaches for optimal treatment of the seizure. Although the actual pathogenesis of epilepsy is still uncertain, recently growing lines of evidence declare that microglia and astrocyte activation, oxidative stress and reactive oxygen species (ROS) production, mitochondria dysfunction, and damage of blood-brain barrier (BBB) are involved in its pathogenesis. Impaired GABAergic function in the brain is probably the most accepted hypothesis regarding the pathogenesis of epilepsy. Clinical neuroimaging of patients and experimental modeling have demonstrated that seizures may induce neuronal apoptosis. Apoptosis signaling pathways are involved in the pathogenesis of several types of epilepsy such as temporal lobe epilepsy (TLE). The quality of life of patients is seriously affected by treatment-related problems and also by unpredictability of epileptic seizures. Moreover, the available antiepileptic drugs (AED) are not significantly effective to prevent epileptogenesis. Thus, novel therapies that are proficient to control seizure in people who are suffering from epilepsy are needed. The preconditioning method promises to serve as an alternative therapeutic approach because this strategy has demonstrated the capability to curtail epileptogenesis. For this reason, understanding of molecular mechanisms underlying brain tolerance induced by preconditioning is crucial to delineate new neuroprotective ways against seizure damage and epileptogenesis. In this review, we summarize the work to date on the pathogenesis of epilepsy and discuss recent therapeutic strategies in the treatment of epilepsy. We will highlight that novel therapy targeting such as preconditioning process holds great promise. In addition, we will also highlight the role of gene reprogramming and mitochondrial biogenesis in the preconditioning-mediated neuroprotective events.
Thyroid hormones (THs) L-thyroxine and L-triiodothyronine, primarily known as metabolism regulators, are tyrosine-derived hormones produced by the thyroid gland. They play an essential role in normal central nervous system development and physiological function. By binding to nuclear receptors and modulating gene expression, THs influence neuronal migration, differentiation, myelination, synaptogenesis and neurogenesis in developing and adult brains. Any uncorrected THs supply deficiency in early life may result in irreversible neurological and motor deficits. The development and function of GABAergic neurons as well as glutamatergic transmission are also affected by THs. Though the underlying molecular mechanisms still remain unknown, the effects of THs on inhibitory and excitatory neurons may affect brain seizure activity. The enduring predisposition of the brain to generate epileptic seizures leads to a complex chronic brain disorder known as epilepsy. Pathologically, epilepsy may be accompanied by mitochondrial dysfunction, oxidative stress and eventually dysregulation of excitatory glutamatergic and inhibitory GABAergic neurotransmission. Based on the latest evidence on the association between THs and epilepsy, we hypothesize that THs abnormalities may contribute to the pathogenesis of epilepsy. We also review gender differences and the presumed underlying mechanisms through which TH abnormalities may affect epilepsy here.
The production of short anticancer peptides in recombinant form is an alternative method for costly chemical manufacturing. However, the limitations of host toxicity, bioactivity and column purification have impaired production in mass quantities. In this study, short cationic peptides were produced in aggregated inclusion bodies by double fusion with a central protein that has anti-cancer activity. The anticancer peptides Tachiplicin I (TACH) and Latarcin 1 (LATA) were fused with the N- and C-terminus of the MAP30 protein, respectively. We successfully produced the recombinant TACH-MAP30-LATA protein and MAP30 alone in E. coli that represented 59% and 68% of the inclusion bodies. The purified form of the inclusion bodies was prepared by eliminating host cell proteins through multiple washing steps and semi-solubilization in alkaline buffer. The purified active protein was recovered by inclusive solubilization at pH 12.5 in the presence of 2 M urea and refolded in alkaline buffer containing oxides and reduced glutathione. The peptide-fusion protein showed lower CC50 values against cancer cells (HepG2, 0.35±0.1 μM and MCF-7, 0.58±0.1 μM) compared with normal cells (WRL68, 1.83±0.2 μM and ARPE19, 2.5±0.1 μM) with outstanding activity compared with its individual components. The presence of the short peptides facilitated the entry of the peptide fusion protein into cancer cells (1.8 to 2.2-fold) compared with MAP30 alone through direct interaction with the cell membrane. The cancer chemotherapy agent doxorubicin showed higher efficiency and selectivity against cancer cells in combination with the peptide- fusion protein. This study provides new data on the mass production of short anticancer peptides as inclusion bodies in E. coli by fusion with a central protein that has similar activity. The product was biologically active against cancer cells compared with normal cells and enhanced the activity and selective delivery of an anticancer chemotherapy agent.
Glycogen synthase kinase 3 (GSK-3) dysregulation plays an important role in the pathogenesis of numerous disorders, affecting the central nervous system (CNS) encompassing both neuroinflammation and neurodegenerative diseases. Several lines of evidence have illustrated a key role of the GSK-3 and its cellular and molecular signaling cascades in the control of neuroinflammation. Glycogen synthase kinase 3 beta (GSK-3β), one of the GSK-3 isomers, plays a major role in neuronal apoptosis and its inhibition decreases expression of alpha-Synuclein (α-Synuclein), which make this kinase an attractive therapeutic target for neurodegenerative disorders. Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Thus, understanding the role of GSK-3β in PD will enhance our knowledge of the basic mechanisms underlying the pathogenesis of this disorder and facilitate the identification of new therapeutic avenues. In recent years, GSK-3β has been shown to play essential roles in modulating a variety of cellular functions, which have prompted efforts to develop GSK-3β inhibitors as therapeutics. In this review, we summarize GSK-3 signaling pathways and its association with neuroinflammation. Moreover, we highlight the interaction between GSK-3β and several cellular processes involved in the pathogenesis of PD, including the accumulation of α-Synuclein aggregates, oxidative stress and mitochondrial dysfunction. Finally, we discuss about GSK-3β inhibitors as a potential therapeutic strategy in PD.
One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation and long-term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long-term potentiation and long-term depression, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14102.