Chronic exposure of homocysteine in mice contributes to dopamine loss by enhancing oxidative stress in nigrostriatum and produces behavioral phenotypes of Parkinson’s disease

AbstractIncreased homocysteine (Hcy) level has been implicated as an independent risk factor for various neurological disorders, including Parkinson’s disease (PD). Hcy has been reported to cause dopaminergic neuronal loss in rodents and causes the behavioral abnormalities. This study is an attempt to investigate molecular mechanisms underlying Hcy-induced dopaminergic neurotoxicity after its chronic systemic administration. Male Swiss albino mice were injected with different doses of Hcy (100 and 250mg/kg; intraperitoneal) for 60 days. Animals subjected to higher doses of Hcy, but not the lower dose, produces motor behavioral abnormalities with significant dopamine depletion in the striatum. Significant inhibition of mitochondrial complex-I activity in nigra with enhanced activity of antioxidant enzymes in the nigrostriatum have highlighted the involvement of Hcy-induced oxidative stress. While, chronic exposure to Hcy neither significantly alters the nigrostriatal glutathione level nor it causes any visible change in tyrosine hydroxylase-immunoreactivity of dopaminergic neurons. The finding set us to hypothesize that the mild oxidative stress due to prolonged Hcy exposure to mice is conducive to striatal dopamine depletion leading to behavioral abnormalities similar to that observed in PD

Contribution of Dopamine in Dopaminergic Neurodegeneration

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive degeneration and loss of nigrostriatal dopaminergic neurons in the midbrain, leading to severe striatal dopamine (DA) depletion resulting in tremor, rigidity, and hypokinesia (Carlsson, 2002). PD is named after James Parkinson who first described the disease as “Shaking Palsy” (Paralysis Agitans) in his classic monograph “An essay on the Shaking Palsy” (Parkinson, 1817). He described the disease as “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace: the senses and intellects being uninjured”. Jean-Martin Charcot (1877) gave PD its present name and elaborated on the description of the disease given by James Parkinson (see Elmer, 2005). Descriptions of the symptoms of PD were found mentioned as early as 5000 B.C in the ancient Indian medical treatise “Charakasamhitha” under the name Kampavata (kampa - tremors). It was also found mentioned in the first Chinese medical text, “Nei Jing”, about 2500 years ago, and in an Egyptian text (Garcia Ruiz, 2004). The only major contention presently is the perception of clinicians that in addition to motor impairments, behavioural dysfunction and cognitive impairment too contribute to the morbidity often seen in PD patients

Cholesterol contributes to dopamine-neuronal loss in MPTP mouse model of Parkinson's disease: Involvement of mitochondrial dysfunctions and oxidative stress.

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

Striatal Dopamine Level Contributes to Hydroxyl Radical Generation and Subsequent Neurodegeneration in the Striatum in 3-nitropropionic Acid-Induced Huntington’s Disease in Rats

We tested the hypothesis that dopamine contributes significantly to the hydroxyl radical (�OH)-induced striatal neurotoxicity caused by 3-nitropropionic acid (3-NP) in a rat model of Huntington’s disease. Dopamine (10–100 mM) or 3-NP (10–1000 mM) individually caused a significant increase in the generation of hydroxyl radical (�OH) in themitochondria, which was synergistically enhanced when the lowest dose of the neurotoxin (10 mM) and dopamine (100 mM) were present together. Similarly, systemic administration of L-DOPA (100–250 mg/kg) and a low dose of 3-NP (10 mg/kg) potentiated �OH generation in the striatum, and the rats exhibited significant decrease in stride length, a direct indication of neuropathology. The pathology was also evident in striatal sections subjected to NeuN immunohistochemistry. The significant changes in stride length, the production of striatal �OH and neuropathological features due to administration of a toxic dose of 3-NP (20 mg/kg) were significantly attenuated by treating the rats with tyrosine hydroxylase inhibitor a-methyl-p-tyrosine prior to 3-NP administration. These results strongly implicate a major contributory role of striatal dopamine in increased generation of �OH, which leads to striatal neurodegeneration and accompanied behavioral changes, in 3-NP model of Huntington’s disease

Endovascular Stem Cell Therapy Post Stroke Rescues Neurons from Endoplasmic Reticulum Stress-Induced Apoptosis by Modulating Brain-Derived Neurotrophic Factor/Tropomyosin Receptor Kinase B Signaling

Ischemic stroke is devastating, with serious long-term disabilities affecting millions of people worldwide. Growing evidence has shown that mesenchymal stem cells (MSCs) administration after stroke provides neuroprotection and enhances the quality of life in stroke patients. Previous studies from our lab have shown that 1 × 105 MSCs administered intra-arterially (IA) at 6 h post stroke provide neuroprotection through the modulation of inflammasome and calcineurin signaling. Ischemic stroke induces endoplasmic reticulum (ER) stress, which exacerbates the pathology. The current study intends to understand the involvement of brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling in preventing apoptosis induced by ER stress post stroke following IA MSCs administration. Ischemic stroke was induced in ovariectomized female Sprague Dawley rats. The MSCs were administered IA, and animals were sacrificed at 24 h post stroke. Infarct area, neurological deficit score, motor coordination, and biochemical parameters were evaluated. The expression of various genes and proteins was assessed. An inhibition study was also carried out to confirm the involvement of BDNF/TrkB signaling in ER stress-induced apoptosis. IA-administered MSCs improved functional outcomes, reduced infarct area, increased neuronal survival, and normalized biochemical parameters. mRNA and protein expression of ER stress markers were reduced, while those of BDNF and TrkB were increased. Reduction in ER stress-mediated apoptosis was also observed. The present study shows that IA MSCs administration post stroke provides neuroprotection and can modulate ER stress-mediated apoptosis via the BDNF/TrkB signaling pathway

A Friend or Foe: Calcineurin across the Gamut of Neurological Disorders

The serine/threonine phosphatase calcineurin (CaN) is a unique but confounding calcium/calmodulin-mediated enzyme. CaN has shown to play essential roles from regulating calcium homeostasis to being an intricate part of learning and memory formation. Neurological disorders, despite differing in their etiology, share similar pathological outcomes, such as mitochondrial dysfunction and apoptotic signaling brought about by excitotoxic elements. CaN, being deeply integrated in vital neuronal functions, may be implicated in various neurological disorders. Understanding the enzyme and its physiological niche in the nervous system is vital in uncovering its roles in the spectrum of brain disorders. By reviewing the crosstalk in different neurological pathologies, a possible grasp of CaN’s complex signaling may lead to forming better neurotherapy. This Outlook attempts to explore the various neuronal functions of CaN and investigate its pervasive role through the gamut of neurological disorders. Calcineurin has vital biological functions with significant roles across different neuropathies. Herein, we present its involvement under varying neuropathological conditions

Advances in Studies on Stroke-Induced Secondary Neurodegeneration (SND) and Its Treatment

Background: The occurrence of secondary neurodegeneration has exclusively been observed after the first incidence of stroke. In humans and rodents, post-stroke secondary neurodegeneration (SND) is an inevitable event that can lead to progressive neuronal loss at a region distant to initial infarct. SND can lead to cognitive and motor function impairment, finally causing dementia. The exact pathophysiology of the event is yet to be explored. It is seen that the thalami, in particular, are susceptible to cause SND. The reason behind this is because the thalamus functioning as the relay center and is positioned as an interlocked structure with direct synaptic signaling connection with the cortex. As SND proceeds, accumulation of misfolded proteins and microglial activation are seen in the thalamus. This leads to increased neuronal loss and worsening of functional and cognitive impairment. Objective: There is a necessity of specific interventions to prevent post-stroke SND, which are not properly investigated to date owing to sparsely reproducible pre-clinical and clinical data. The basis of this review is to investigate about post-stroke SND and its updated treatment approaches carefully. Methods: Our article presents a detailed survey of advances in studies on stroke-induced secondary neurodegeneration (SND) and its treatment. Results: This article aims to put forward the pathophysiology of SND. We have also tabulated the latest treatment approaches along with different neuroimaging systems that will be helpful for future reference to explore. Conclusion: In this article, we have reviewed the available reports on SND pathophysiology, detection techniques, and possible treatment modalities that have not been attempted to date