With increasing prevalence, chronic kidney disease (CKD) has become a global health problem. Due to the retention of uremic toxins, electrolytes and water, and the resultant metabolic disturbances, ...CKD affects several organs, including the nervous system. Thus, CKD patients suffer from several neurological complications, including dementia, cognitive impairment, motor abnormalities, depression, and mood and sleep disturbances. However, the mechanisms underlying the neurological complications are least elucidated. We have recently reported a highly reproducible mice model of CKD induced by high adenine diet, which exhibited psychomotor behavioral abnormalities and blood-brain barrier disruption. In the present study, using the mice model, we have investigated psycho-motor and cognitive behaviour, and the neurochemical and histopathological alterations in brain relevant to the observed behavioural abnormalities. The results demonstrate global loss of Acetylcholinesterase activity, and decrease in neuronal arborisation and dendritic spine density in discrete brain regions, of the CKD mice. Oxidative stress, inflammation, and mitochondrial dysfunctions were found in specific brain regions of the mice, which have been regarded as the underlying causes of the observed neurochemical and histopathological alterations. Thus, the present study is of immense importance, and has therapeutic implications in the management of CKD-associated neurological complications.
Ischemic stroke is one of the significant causes of morbidity and mortality, affecting millions of people across the globe. Cell injury in the infarct region is an inevitable consequence of focal ...cerebral ischemia. Subsequent reperfusion exacerbates the harmful effect and increases the infarct volume. These cellular injuries follow either a regulated pathway involving tightly structured signaling cascades and molecularly defined effector mechanisms or a non-regulated pathway, also known as accidental cell death, where the process is biologically uncontrolled. Classical cell death pathways are long established and well reported in several articles that majorly define apoptotic cell death. A recent focus on cell death study also considers investigation on non-classical pathways that are tightly regulated, may or may not involve caspases, but non-apoptotic. Pathological cell death is a cardinal feature of different neurodegenerative diseases. Although ischemia cannot be classified as a neurodegenerative disease, it is a cerebrovascular event where the infarct region exhibits aberrant cell death. Over the past few decades, several therapeutic options have been implicated for ischemic stroke. However, their use has been hampered owing to the number of limitations that they possess. Ischemic penumbral neurons undergo apoptosis and become dysfunctional; however, they are salvageable. Thus, understanding the role of different cell death pathways is crucial to aid in the modern treatment of protecting apoptotic neurons.
Hypercholesterolemia is a known contributor to the pathogenesis of Alzheimer's disease while its role in the occurrence of Parkinson's disease (PD) is only conjecture and far from conclusive. Altered ...antioxidant homeostasis and mitochondrial functions are the key mechanisms in loss of dopaminergic neurons in the substantia nigra (SN) region of the midbrain in PD. Hypercholesterolemia is reported to cause oxidative stress and mitochondrial dysfunctions in the cortex and hippocampus regions of the brain in rodents. However, the impact of hypercholesterolemia on the midbrain dopaminergic neurons in animal models of PD remains elusive. We tested the hypothesis that hypercholesterolemia in MPTP model of PD would potentiate dopaminergic neuron loss in SN by disrupting mitochondrial functions and antioxidant homeostasis. It is evident from the present study that hypercholesterolemia in naïve animals caused dopamine neuronal loss in SN with subsequent reduction in striatal dopamine levels producing motor impairment. Moreover, in the MPTP model of PD, hypercholesterolemia exacerbated MPTP-induced reduction of striatal dopamine as well as dopaminergic neurons in SN with motor behavioral depreciation. Activity of mitochondrial complexes, mainly complex-I and III, was impaired severely in the nigrostriatal pathway of hypercholesterolemic animals treated with MPTP. Hypercholesterolemia caused oxidative stress in the nigrostriatal pathway with increased generation of hydroxyl radicals and enhanced activity of antioxidant enzymes, which were further aggravated in the hypercholesterolemic mice with Parkinsonism. In conclusion, our findings provide evidence of increased vulnerability of the midbrain dopaminergic neurons in PD with hypercholesterolemia.
Meta-analyses of tea consumption and reduced risk of Parkinson's disease have thrown light in the pathway of exploring beneficial properties of tea components. On the basis of dry mass, a typical ...black or green tea beverage contains approximately 6% of free amino acids, which impart high quality, taste and distinctive aroma to the tea infusion. L-theanine (chemically known as γ-glutamylethylamide) is a non-proteinogenic amino acid of tea that takes part in the biosynthesis of its polyphenols. Recently discovered neuroprotective effects of L-theanine can be attributed to its structural analogy with glutamate, the principal excitatory neurotransmitter in brain. This unique amino acid also bears a potential to ameliorate the pathophysiological changes associated with Parkinson's disease as it displays antioxidant and anti-inflammatory properties, improves motor behavioral abnormalities, increases dopamine availability and may cause a favorable downshift in neurodegeneration due to glutamate excitotoxicity. To gain an explicit understanding of the role of L-theanine, this review article is the first one to focus on its mechanism of neuromodulatory action and to critically evaluate the possibilities of employing this bioactive amide in the forage of anti-Parkinsonian medication. We also hypothesize the idea of L-theanine being a potent natural agent against L-DOPA induced dyskinesia, since long-term reliance on dopamine replacement therapy is linked with elevation in glutamate receptor activity.
•Increased level of extracellular glutamate is a phenomenon associated with Parkinson's disease pathophysiology.•L-theanine bears the potential to attenuate neuronal excitotoxicity due to glutamatergic upsurge.•L-theanine may be an effective medication against long-term L-DOPA induced dyskinesia.
Apoptosis mediated by endoplasmic reticulum (ER) stress plays a crucial role in several neurovascular disorders, including ischemia/reperfusion injury (I/R injury). Previous in vitro and in vivo ...studies have suggested that following I/R injury, ER stress is vital for mediating CCAT-enhancer-binding protein homologous protein (CHOP) and caspase-12-dependent apoptosis. However, its modulation in the presence of stem cells and the underlying mechanism of cytoprotection remains elusive. In vivo studies from our lab have reported that post-stroke endovascular administration of stem cells renders neuroprotection and regulates apoptosis mediated by ER stress. In the current study, a more robust in vitro validation has been undertaken to decipher the mechanism of stem cell-mediated cytoprotection. Results from our study have shown that oxygen–glucose deprivation/reoxygenation (OGD/R) potentiated ER stress and apoptosis in the pheochromocytoma 12 (PC12) cell line as evident by the increase of protein kinase R (PKR)-like ER kinase (p-PERK), p-Eukaryotic initiation factor 2α subunit (EIF2α), activation transcription factor 4 (ATF4), CHOP, and caspase 12 expressions. Following the co-culture of PC12 cells with MSCs, ER stress was significantly reduced, possibly via modulating the brain-derived neurotrophic factor (BDNF) signaling. Furthermore, inhibition of BDNF by inhibitor K252a abolished the protective effects of BDNF secreted by MSCs following OGD/R. Our study suggests that inhibition of ER stress-associated apoptotic pathway with MSCs coculture following OGD/R may help to alleviate cellular injury and further substantiate the use of stem cells as a therapeutic modality toward neuroprotection following hypoxic injury or stroke in clinical settings.
Although the etiology of Parkinson’s disease (PD) is poorly understood, studies in animal models revealed loss of dopamine and the dopaminergic neurons harbouring the neurotransmitter to be the ...principal cause behind this neuro-motor disorder. Neuroinflammation with glial cell activation is suggested to play a significant role in dopaminergic neurodegeneration. Several biomolecules have been reported to confer dopaminergic neuroprotection in different animal models of PD, owing to their anti-inflammatory potentials. Garcinol is a tri-isoprenylated benzophenone isolated from
Garcinia sp.
and accumulating evidences suggest that this molecule could provide neuroprotection by modulating oxidative stress and inflammation. However, direct evidence of dopaminergic neuroprotection by garcinol in the pre-clinical model of PD is not yet reported. The present study aims to investigate whether administration of garcinol in the MPTP mouse model of PD may ameliorate the cardinal motor behavioural deficits and prevent the loss of dopaminergic neurons. As expected, garcinol blocked the parkinsonian motor behavioural deficits which include akinesia, catalepsy, and rearing anomalies in the mice model. Most importantly, the degeneration of dopaminergic cell bodies in the substantia nigra region was significantly prevented by garcinol. Furthermore, garcinol reduced the inflammatory marker, glial fibrillary acidic protein, in the substantia nigra region. Since glial hyperactivation-mediated inflammation is inevitably associated with the loss of dopaminergic neurons, our study suggests the anti-inflammatory role of garcinol in facilitating dopaminergic neuroprotection in PD mice. Hence, in the light of the present study, it is suggested that garcinol is an effective anti-parkinsonian agent to block motor behavioural deficits and dopaminergic neurodegeneration in PD.
Post-stroke edema and upregulation of aquaporin 4 (AQP4) water transport channels play a significant role in the progression of stroke pathology and deteriorating stroke outcomes. Prior studies from ...our lab have demonstrated the safety and efficacy of intra-arterial (IA) 1 × 10
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mesenchymal stem cells (MSCs) administration post-stroke towards functional restoration and neuroprotection. Protein kinases have been reported to be involved in the signaling cascade of edema, with evidence supporting both its upregulation and downregulation at 24 h post-stroke. Among different protein kinase C (PKC) isoforms, the δ isoform is widely reported to play a pivotal role in the progression of ischemic reperfusion injury. Our present study aims to decipher the molecular mechanism of post-stroke IA MSCs mediated alleviation of perifocal vasogenic edema by PKCδ-mediated AQP4 regulation. Ovariectomized female SD rats were infused with 1 × 10
5
IA MSCs at 6 h post middle cerebral artery occlusion (MCAo). Animals were evaluated for behavioral and functional outcomes. Brains were harvested for evaluating infarct size and brain edema. Further, brain tissues were used for biochemical and molecular studies to decipher the possible molecular mechanism related to the regulation of PKCδ-mediated AQP4 expression. 1 × 10
5
IA MSCs at 6 h post-stroke confers neuroprotection as evident by the reduction in infarct size, edema, and improvement of functional outcome. An increase in GSH and catalase and a reduction in nitrite and MDA were observed along with a decrease in AQP4 and PKCδ expressions within the cortical brain regions of IA MSC–infused animals. The study gives preliminary evidence that IA MSCs administration post-stroke modulates PKCδ to regulate AQP4 expression which alleviates vasogenic edema towards neuroprotection. The study is novel and clinically relevant as no previous studies have looked into this aspect following IA delivery of stem cells in an animal model of ischemic stroke.
Neurological disorders have complicated pathophysiology that may involve several genetic mutations. Conventional treatment has limitations as they only treat apparent symptoms. Although, personalized ...medicine is emerging as a promising neuro-intervention, lack of precision is the major pitfall. Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is evolving as a technological platform that may overcome the therapeutic limitations towards precision medicine. In the future, targeting genes in neurological disorders may be the mainstay of modern therapy. The present review on CRISPR/Cas9 and its application in various neurological disorders may provide a platform for its future clinical relevance towards developing precise and personalized medicine.
Summary
Neurodegeneration is characterized by gradual onset and limited availability of specific biomarkers. Apart from various aetiologies such as infection, trauma, genetic mutation, the ...interaction between the immune system and CNS is widely associated with neuronal damage in neurodegenerative diseases. The immune system plays a distinct role in disease progression and cellular homeostasis. It induces cellular and humoral responses, and enables tissue repair, cellular healing and clearance of cellular detritus. Aberrant and chronic activation of the immune system can damage healthy neurons. The pro‐inflammatory mediators secreted by chief innate immune components, the complement system, microglia and inflammasome can augment cytotoxicity. Furthermore, these inflammatory mediators accelerate microglial activation resulting in progressive neuronal loss. Various animal studies have been carried out to unravel the complex pathology and ascertain biomarkers for these harmful diseases, but have had limited success. The present review will provide a thorough understanding of microglial activation, complement system and inflammasome generation, which lead the healthy brain towards neurodegeneration. In addition to this, possible targets of immune components to confer a strategic treatment regime for the alleviation of neuronal damage are also summarized.
The present review aimed to provide a thorough information to the readers about microglial activation, complement system and inflammasome generation. Further, we discuss how the processes involved in these system lead the healthy brain towards neurodegeneration. Also discussed are the possible targets of immune components to confer a strategic treatment regime for the alleviation of neuronal damage.
: We tested the hypothesis that melatonin regulates formation of 6‐hydroxydopamine (6‐OHDA) in the brain and thereby protects animals from dopaminergic neurotoxicity and the development of ...parkinsonism in animals. Employing a ferrous‐ascorbate‐dopamine (FAD) hydroxyl radical (•OH) generating system, in the present study we demonstrate a dose‐dependent attenuation of 6‐OHDA generation by melatonin in vitro. Intra‐median forebrain bundle infusion of FAD caused significant depletion of striatal dopamine (DA), which was blocked by melatonin. Per‐oral administration of l‐3,4‐dihydroxyphenylalanine (l‐DOPA) for 7 days caused a dose‐dependent increase in the formation of 6‐OHDA in the mouse striatum, which was increased synergistically by the systemic administration of the parkinsonian neurotoxin, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) on the 7th day of l‐DOPA treatment. Melatonin treatment significantly attenuated both the l‐DOPA and MPTP‐induced increases in the levels of striatal 6‐OHDA, and protected against striatal DA depletion caused by the neurotoxin. These observations suggest a novel mode of melatonin‐induced dopaminergic neuroprotection in two models of Parkinson’s disease, and suggest the possible therapeutic use of this well‐known antioxidant indoleamine neurohormone in parkinsonism.
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