Preclinical study of dimebon on β-amyloid-mediated neuropathology in Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Dimebon is a retired non-selective antihistamine drug currently being investigated as a therapeutic agent for the treatment of Alzheimer's disease (AD). Results from several completed clinical trials are mixed and contradictory. Proper interpretations of these clinical observations, as well as future development of dimebon in AD treatment are complicated by the lack of concrete information on the mechanisms by which dimebon might benefit AD.</p> <p>Results</p> <p>The present studies are designed specifically to assess whether dimebon might modulate β-amyloid (Aβ)-mediated responses which are central to the development and progression of AD dementia. We found that dimebon is bioavailable in the brains of mice following oral administration. AD mice chronically treated with dimebon exhibited a trend of improvement in spatial memory function without affecting the levels of total Aβ as well as soluble oligomeric Aβ in the brain. The same trend of behavior improvement is also seen in wild type animals chronically treated with dimebon.</p> <p>Conclusion</p> <p>Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function independent of Alzheimer's disease-type Aβ-related mechanisms or global energy metabolism in the brain. Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington's disease, or in the aging population. Additional studies will be necessary to clarify the mechanisms by which dimebon might directly or indirectly benefit cognitive function.</p

Unconventional animal models for traumatic brain injury and chronic traumatic encephalopathy

Traumatic brain injury (TBI) is one of the main causes of death worldwide. It is a complex injury that influences cellular physiology, causes neuronal cell death, and affects molecular pathways in the brain. This in turn can result in sensory, motor, and behavioral alterations that deeply impact the quality of life. Repetitive mild TBI can progress into chronic traumatic encephalopathy (CTE), a neurodegenerative condition linked to severe behavioral changes. While current animal models of TBI and CTE such as rodents, are useful to explore affected pathways, clinical findings therein have rarely translated into clinical applications, possibly because of the many morphofunctional differences between the model animals and humans. It is therefore important to complement these studies with alternative animal models that may better replicate the individuality of human TBI. Comparative studies in animals with naturally evolved brain protection such as bighorn sheep, woodpeckers, and whales, may provide preventive applications in humans. The advantages of an in-depth study of these unconventional animals are threefold. First, to increase knowledge of the often-understudied species in question; second, to improve common animal models based on the study of their extreme counterparts; and finally, to tap into a source of biological inspiration for comparative studies and translational applications in humans

Mitochondrial Dysfunction in Parkinson’s Disease

Parkinson’s disease (PD, also referred to as sporadic or idiopathic PD and primary parkinsonism) is a progressive motor disorder that occurs in old age and is characterized by resting tremor, rigidity and slowness of movement. It is named after James Parkinson, the physician whose description of PD is one of the early authoritative accounts of the disease(Parkinson 1817). He called it the shaking palsy or paralysis agitans. Earlier references to the symptoms of PD may be found in Indian and Egyptian texts (García Ruiz 2004).Parkinson, referring to previous accounts of tremor and palsy by Galen, Sylvius de la Boë, Boissier de Sauvages and Gaubius, stressed on the distinctive tremor that occurs in the absence of voluntary activity in PD patients (resting tremor) and the tendency of patients to run when attempting to walk (festinating gait). He also described the slowness in initiating movement (bradykinesia), freezing (akinesia), postural instability, difficulty in performing complex activities like writing, sleep disturbance and drooling seen in PD. Jean-Martin Charcot (1877) gave PD its present name and added to the description given by Parkinson the symptoms of masked facies, rigidity and the non-motor symptoms (reviewed by Elmer 2005). The secondary non-motor symptoms of PD include autonomic dysfunction, depression and dementia

Peroxisome Proliferator Activator Receptor Gamma Coactivator-1α Overexpression in Amyotrophic Lateral Sclerosis: A Tale of Two Transgenics

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder manifesting with upper and lower neuron loss, leading to impairments in voluntary muscle function and atrophy. Mitochondrial dysfunction in metabolism and morphology have been implicated in the pathogenesis of ALS, including atypical oxidative metabolism, reduced mitochondrial respiration in muscle, and protein aggregates in the mitochondrial outer membrane. Peroxisome proliferator-activated receptor &gamma; coactivator-1&alpha; (PGC-1&alpha;) plays an essential role in the regulation of mitochondrial biogenesis, the process by which existing mitochondria grow and divide. PGC-1&alpha; has been previously reported to be downregulated in the spinal cord of individuals with ALS. Towards targeting PGC-1&alpha; as a therapeutic mechanism, we have previously reported improved motor function and survival in the SOD1G93A mouse model of ALS by neuron-specific over-expression of PGC-1&alpha; under a neuron-specific enolase (NSE) promoter. As pharmacological intervention targeting PGC-1&alpha; would result in whole-body upregulation of this transcriptional co-activator, in the current study we investigated whether global expression of PGC-1&alpha; is beneficial in a SOD1G93A mouse model, by generating transgenic mice with PGC-1&alpha; transgene expression driven by an actin promoter. Actin-PGC-1&alpha; expression levels were assayed and confirmed in spinal cord, brain, muscle, liver, kidney, and spleen. To determine the therapeutic effects of global expression of PGC-1&alpha;, wild-type, actin-PGC-1&alpha;, SOD1G93A, and actin-PGC-1&alpha;/SOD1G93A animals were monitored for weight loss, motor performance by accelerating rotarod test, and survival. Overexpression of actin-PGC-1&alpha; did not confer significant improvement in these assessed outcomes. A potential explanation for this difference is that the actin promoter may not induce levels of PGC-1&alpha; relevant to disease pathophysiology in the cells that are specifically relevant to the pathogenesis of ALS. This evidence strongly supports future therapeutic approaches that target PGC-1&alpha; primarily in neurons

Reduced NADH Coenzyme Q Dehydrogenase Activity in Platelets of Parkinson's Disease, but not Parkinson plus Patients, from an Indian Population.

The observation of decline in mitochondrial electron transport chain function, specifically at complex I, in patients with Parkinson's disease (PD) has been reported by several groups. This study investigates whether a defect of mitochondrial function is present in the platelets of PD patients from an Indian population. We found that the NADH dehydrogenase activity in the platelets of PD patients is lower than that in healthy ageand gender-matched controls, while the succinate dehydrogenase activity was similar in both groups. Furthermore, there was no change in either of the activities in patients with Parkinson plus syndrome or atypical parkinsonism. This is the first report indicating a decline in mitochondrial function in the platelets of PD patients from the Indian population, offering further support to the role of a mitochondrial defect in PD

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

Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) is a principal regulator of mitochondrial biogenesis and oxidative metabolism. Results In this study, we examined whether PGC-1α plays a protective role in ALS by using a double transgenic mouse model where PGC-1α is over-expressed in an SOD1 transgenic mouse (TgSOD1-G93A/PGC-1α). Our results indicate that PGC-1α significantly improves motor function and survival of SOD1-G93A mice. The behavioral improvements were accompanied by reduced blood glucose level and by protection of motor neuron loss, restoration of mitochondrial electron transport chain activities and inhibition of stress signaling in the spinal cord. Conclusion Our results demonstrate that PGC-1α plays a beneficial role in a mouse model of ALS, suggesting that PGC-1α may be a potential therapeutic target for ALS therapy.</p