Intranasal Administration of Forskolin and Noopept Reverses Parkinsonian Pathology in PINK1 Knockout Rats.

Parkinson's Disease (PD) is a brain-degenerative disorder characterized by a progressive loss of midbrain dopamine neurons. Current standard-of-care includes oral administration of Levodopa to address motor symptoms, but this treatment is not disease-modifying. A reduction in Protein Kinase A (PKA) signaling and neurotrophic support contributes to PD pathology. We previously showed that enhancing PKA activity in the brain via intraperitoneal administration of Forskolin in Parkinsonian rats (PINK1 knockout) abrogate motor symptoms and loss of midbrain dopamine neurons. Given that intraperitoneal administration is invasive, we hypothesized that intranasal administration of Forskolin and a second nootropic agent (Noopept) could reverse PD pathology efficiently. Results show that intranasal administration of a formulation (CNS/CT-001) containing Forskolin (10 µM) and Noopept (20 nM) significantly reversed motor symptoms, loss of hind limb strength, and neurodegeneration of midbrain dopamine neurons in PINK1-KO rats and is indistinguishable from wild-type (WT) rats; therapeutic effects associated with increased PKA activity and levels of BDNF and NGF in the brain. Intranasal administration of CNS/CT-001, but not Forskolin, significantly decreased the number of α-synuclein aggregates in the cortex of PINK1-KO rats, and is indistinguishable from WT rats. Overall, we show proof of concept that intranasal administration of CNS/CT-001 is a non-invasive, disease-modifying formulation for PD.

Chronic AT1 blockade improves hyperglycemia by decreasing adipocyte inflammation and decreasing hepatic PCK1 and G6PC1 expression in obese rats.

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT1) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT1 blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT1. We measured adipocyte morphology along with TNF-α expression, F4/80- and CD11c-positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before (T0), 60 (T60) and 120 (T120) min after an acute glucose challenge in the following groups of male rats: 1) Long-Evans Tokushima Otsuka (LETO; lean control; n = 5/time point), 2) obese Otsuka Long Evans Tokushima Fatty (OLETF; n = 7 or 8/time point), and 3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 7 or 8/time point). AT1 blockade decreased adipocyte TNF-α expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at T60, IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT1 blockade increased glucose transporter-4 (GLUT4) protein expression in ARB compared with OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT1 blockade decreased hepatic Pck1 and G6pc1 mRNA expressions. Collectively, these results suggest that chronic AT1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis.NEW & NOTEWORTHY Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic Pck1 and G6pc1 mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.

Sparse and Random Sampling Techniques for High-Resolution, Full-Field, BSS-Based Structural Dynamics Identification from Video.

Video-based techniques for identification of structural dynamics have the advantage that they are very inexpensive to deploy compared to conventional accelerometer or strain gauge techniques. When structural dynamics from video is accomplished using full-field, high-resolution analysis techniques utilizing algorithms on the pixel time series such as principal components analysis and solutions to blind source separation the added benefit of high-resolution, full-field modal identification is achieved. An important property of video of vibrating structures is that it is particularly sparse. Typically video of vibrating structures has a dimensionality consisting of many thousands or even millions of pixels and hundreds to thousands of frames. However the motion of the vibrating structure can be described using only a few mode shapes and their associated time series. As a result, emerging techniques for sparse and random sampling such as compressive sensing should be applicable to performing modal identification on video. This work presents how full-field, high-resolution, structural dynamics identification frameworks can be coupled with compressive sampling. The techniques described in this work are demonstrated to be able to recover mode shapes from experimental video of vibrating structures when 70% to 90% of the frames from a video captured in the conventional manner are removed.

Adipose transcriptome analysis provides novel insights into molecular regulation of prolonged fasting in northern elephant seal pups.

The physiological and cellular adaptations to extreme fasting in northern elephant seals ( Mirounga angustirostris, NES) are remarkable and may help to elucidate endocrine mechanisms that regulate lipid metabolism and energy homeostasis in mammals. Recent studies have highlighted the importance of thyroid hormones in the maintenance of a lipid-based metabolism during prolonged fasting in weaned NES pups. To identify additional molecular regulators of fasting, we used a transcriptomics approach to examine changes in global gene expression profiles before and after 6-8 wk of fasting in weaned NES pups. We produced a de novo assembly and identified 98 unique protein-coding genes that were differentially expressed between early and late fasting. Most of the downregulated genes were associated with lipid, carbohydrate, and protein metabolism. A number of downregulated genes were also associated with maintenance of the extracellular matrix, consistent with tissue remodeling during weight loss and the multifunctional nature of blubber tissue, which plays both metabolic and structural roles in marine mammals. Using this data set, we predict potential mechanisms by which NES pups sustain metabolism and regulate adipose stores throughout the fast, and provide a valuable resource for additional studies of extreme metabolic adaptations in mammals.

Thyroid Hormone Regulation and Insulin Resistance: Insights From Animals Naturally Adapted to Fasting.

The contribution of thyroidal status in insulin signaling and glucose homeostasis has been implicated as a potential pathophysiological factor in humans, but the specific mechanisms remain largely elusive. Fasting induces changes in both thyroid hormone secretion and insulin signaling. Here, we explore how mammals that undergo natural, prolonged bouts of fasting provide unique insight into evolved physiological adaptations that allow them to tolerate such conditions despite intermittent states of reversible insulin resistance. Such insights from nature may provide clues to better understand the basis of thyroidal involvement in insulin dysregulation in humans.

Angiotensin receptor and tumor necrosis factor-α activation contributes to glucose intolerance independent of systolic blood pressure in obese rats.

Pathological activation of the renin-angiotensin system and inflammation are associated with hypertension and the development of metabolic syndrome (MetS). The contributions of angiotensin receptor type 1 (AT1) activation, independent of blood pressure, and inflammation to glucose intolerance and renal damage are not well defined. Using a rat model of MetS, we hypothesized that the onset of glucose intolerance is primarily mediated by AT1 activation and inflammation independent of elevated systolic blood pressure (SBP). To address this hypothesis, we measured changes in SBP, adiposity, plasma glucose and triglyceride levels, and glucose tolerance in six groups of rats: 1) lean, strain control Long-Evans Tokushima Otsuka (LETO; n = 5), 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF; n = 8), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n = 8), 4) OLETF + tumor necrosis factor-α (TNF-α) inhibitor (ETAN; 1.25 mg etanercept/kg; n = 6), 5) OLETF + TNF-α inhibitor + angiotensin receptor blocker (ETAN+ARB; 1.25 mg etanercept/kg + 10 mg olmesartan/kg; n = 6), and 6) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n = 7). ARB and ETAN+ARB were most effective at decreasing SBP in OLETF, and ETAN did not offer any additional reduction. Glucose tolerance improved in ARB, ETAN, and ETAN+ARB compared with OLETF, whereas CCB had no detectable effect. Furthermore, all treatments reduced adiposity, whereas ETAN alone normalized urinary albumin excretion. These results suggest that AT1 activation and inflammation are primary factors in the development of glucose intolerance in a setting of MetS and that the associated increase in SBP is primarily mediated by AT1 activation.

Thyroid hormone-stimulated increases in PGC-1α and UCP2 promote life history-specific endocrine changes and maintain a lipid-based metabolism.

Thyroid hormones (THs) regulate metabolism, but are typically suppressed during times of stressful physiological conditions, including fasting. Interestingly, prolonged fasting in northern elephant seal pups is associated with reliance on a lipid-based metabolism and increased levels of circulating THs that are partially attributed to active secretion as opposed to reduced clearance. This apparent paradox is coupled with complementary increases in cellular TH-mediated activity, suggesting that in mammals naturally adapted to prolonged fasting, THs are necessary to support metabolism. However, the functional relevance of this physiological paradox has remained largely unexplored, especially as it relates to the regulation of lipids. To address the hypothesis that TSH-mediated increase in THs contributes to lipid metabolism, we infused early and late-fasted pups with TSH and measured several key genes in adipose and muscle, and plasma hormones associated with regulation of lipid metabolism. TSH infusion increased the mRNA expressions of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) more than 6.5-fold at 60 min in muscle, and expression of uncoupling protein 2 (UCP2) more than 27-fold during the early fast at 60 min, in adipose. Additionally, during the late fast period, the protein content of adipose CD36 increased 1.1-fold, and plasma nonesterified fatty acid (NEFA) concentrations increased 25% at 120 min, with NEFA levels returning to baseline after 24 h. We show that the TSH-induced increases in THs in fasting pups are functional and likely contribute to the maintenance of a lipid-based metabolism.

Increased sensitivity of thyroid hormone-mediated signaling despite prolonged fasting.

Thyroid hormones (TH) can increase cellular metabolism. Food deprivation in mammals is typically associated with reduced thyroid gland responsiveness, in an effort to suppress cellular metabolism and abate starvation. However, in prolonged-fasted, elephant seal pups, cellular TH-mediated proteins are up-regulated and TH levels are maintained with fasting duration. The function and contribution of the thyroid gland to this apparent paradox is unknown and physiologically perplexing. Here we show that the thyroid gland remains responsive during prolonged food deprivation, and that its function and production of TH increase with fasting duration in elephant seals. We discovered that our modeled plasma TH data in response to exogenous thyroid stimulating hormone predicted cellular signaling, which was corroborated independently by the enzyme expression data. The data suggest that the regulation and function of the thyroid gland in the northern elephant seal is atypical for a fasted animal, and can be better described as, "adaptive fasting". Furthermore, the modeling data help substantiate the in vivo responses measured, providing unique insight on hormone clearance, production rates, and thyroid gland responsiveness. Because these unique endocrine responses occur simultaneously with a nearly strict reliance on the oxidation of lipid, these findings provide an intriguing model to better understand the TH-mediated reliance on lipid metabolism that is not otherwise present in morbidly obese humans. When coupled with cellular, tissue-specific responses, these data provide a more integrated assessment of thyroidal status that can be extrapolated for many fasting/food deprived mammals.

Glucose delays the insulin-induced increase in thyroid hormone-mediated signaling in adipose of prolong-fasted elephant seal pups.

Prolonged food deprivation in mammals typically reduces glucose, insulin, and thyroid hormone (TH) concentrations, as well as tissue deiodinase (DI) content and activity, which, collectively, suppress metabolism. However, in elephant seal pups, prolonged fasting does not suppress TH levels; it is associated with upregulation of adipose TH-mediated cellular mechanisms and adipose-specific insulin resistance. The functional relevance of this apparent paradox and the effects of glucose and insulin on TH-mediated signaling in an insulin-resistant tissue are not well defined. To address our hypothesis that insulin increases adipose TH signaling in pups during extended fasting, we assessed the changes in TH-associated genes in response to an insulin infusion in early- and late-fasted pups. In late fasting, insulin increased DI1, DI2, and THrß-1 mRNA expression by 566%, 44%, and 267% at 60 min postinfusion, respectively, with levels decreasing by 120 min. Additionally, we performed a glucose challenge in late-fasted pups to differentiate between insulin- and glucose-mediated effects on TH signaling. In contrast to the insulin-induced effects, glucose infusion did not increase the expressions of DI1, DI2, and THrß-1 until 120 min, suggesting that glucose delays the onset of the insulin-induced effects. The data also suggest that fasting duration increases the sensitivity of adipose TH-mediated mechanisms to insulin, some of which may be mediated by increased glucose. These responses appear to be unique among mammals and to have evolved in elephant seals to facilitate their adaptation to tolerate an extreme physiological condition.

MicroRNAs as potential biomarkers for diagnosis of schizophrenia and influence of antipsychotic treatment.

ABSTRACT: Characterized by positive symptoms (such as changes in behavior or thoughts, including delusions and hallucinations), negative symptoms (such as apathy, anhedonia, and social withdrawal), and cognitive impairments, schizophrenia is a chronic, severe, and disabling mental disorder with late adolescence or early adulthood onset. Antipsychotics are the most commonly used drugs to treat schizophrenia, but those currently in use do not fully reverse all three types of symptoms characterizing this condition. Schizophrenia is frequently misdiagnosed, resulting in a delay of or inappropriate treatment. Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of schizophrenia. The recent studies reviewed included microRNA profiling in blood- and urine-based materials and nervous tissue materials. From the studies that had validated the preliminary findings, potential candidate biomarkers for schizophrenia in adults could be miR-22-3p, -30e-5p, -92a-3p, -148b-5p, -181a-3p, -181a-5p, -181b-5p, -199b-5p, -137 in whole blood, and miR-130b, -193a-3p in blood plasma. Antipsychotic treatment of schizophrenia patients was found to modulate the expression of certain microRNAs including miR-130b, -193a-3p, -132, -195, -30e, -432 in blood plasma. Further studies are warranted with adolescents and young adults having schizophrenia and consideration should be given to using animal models of the disorder to investigate the effect of suppressing or overexpressing specific microRNAs.

Prolonged food deprivation increases mRNA expression of deiodinase 1 and 2, and thyroid hormone receptor ß-1 in a fasting-adapted mammal.

Food deprivation in mammals is typically associated with reduced thyroid hormone (TH) concentrations and deiodinase content and activity to suppress metabolism. However, in prolonged-fasted, metabolically active elephant seal pups, TH levels are maintained, if not elevated. The functional relevance of this apparent paradox is unknown and demonstrates variability in the regulation of TH levels, metabolism and function in food-deprived mammals. To address our hypothesis that cellular TH-mediated activity is upregulated with fasting duration, we quantified the mRNA expression and protein content of adipose and muscle deiodinase type I (DI1) and type II (DI2), and TH receptor beta-1 (THrß-1) after 1, 3 and 7 weeks of fasting in northern elephant seal pups (N=5-7 per week). Fasting did not decrease the concentrations of plasma thyroid stimulating hormone, total triiodothyronine (tT3), free T3, total thyroxine (tT4) or free T4, suggesting that the hypothalamic-pituitary-thyroid axis is not suppressed, but rather maintained during fasting. Mean mRNA expression of adipose DI1 and DI2 increased threefold and fourfold, respectively, and 20- and 30-fold, respectively, in muscle. With the exception of adipose DI1, protein expression of adipose DI2 and muscle DI1 and DI2 increased twofold to fourfold. Fasting also increased adipose (fivefold) and muscle (fourfold) THrß-1 mRNA expression, suggesting that the mechanisms mediating cellular TH activity are upregulated with prolonged fasting. The data demonstrate a unique, atypical mechanism of TH activity and regulation in mammals adapted to prolonged food deprivation in which the potential responsiveness of peripheral tissues and cellular TH activity are increased, which may contribute to their lipid-based metabolism.

MicroRNAs as potential biomarkers in temporal lobe epilepsy and mesial temporal lobe epilepsy.

Temporal lobe epilepsy is the most common form of focal epilepsy in adults, accounting for one third of all diagnosed epileptic patients, with seizures originating from or involving mesial temporal structures such as the hippocampus, and many of these patients being refractory to treatment with anti-epileptic drugs. Temporal lobe epilepsy is the most common childhood neurological disorder and, compared with adults, the symptoms are greatly affected by age and brain development. Diagnosis of temporal lobe epilepsy relies on clinical examination, patient history, electroencephalographic recordings, and brain imaging. Misdiagnosis or delay in diagnosis is common. A molecular biomarker that could distinguish epilepsy from healthy subjects and other neurological conditions would allow for an earlier and more accurate diagnosis and appropriate treatment to be initiated. Among possible biomarkers of pathological changes as well as potential therapeutic targets in the epileptic brain are microRNAs. Most of the recent studies had performed microRNA profiling in body fluids such as blood plasma and blood serum and brain tissues such as temporal cortex tissue and hippocampal tissue. A large number of microRNAs were dysregulated when compared to healthy controls and with some overlap between individual studies that could serve as potential biomarkers. For example, in adults with temporal lobe epilepsy, possible biomarkers are miR-199a-3p in blood plasma and miR-142-5p in blood plasma and blood serum. In adults with mesial temporal lobe epilepsy, possible biomarkers are miR-153 in blood plasma and miR-145-3p in blood serum. However, in many of the studies involving patients who receive one or several anti-epileptic drugs, the influence of these on microRNA expression in body fluids and brain tissues is largely unknown. Further studies are warranted with children with temporal lobe epilepsy and consideration should be given to utilizing mouse or rat and non-human primate models of temporal lobe epilepsy. The animal models could be used to confirm microRNA findings in human patients and to test the effects of targeting specific microRNAs on disease progression and behavior.

MicroRNAs in mouse and rat models of experimental epilepsy and potential therapeutic targets.

Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chronic seizures are difficult to cure. MicroRNAs are widely expressed in the central nervous system and play important roles in the pathogenesis of several neurological disorders, including epilepsy. A variety of animals (mostly mice and rats) have been used to induce experimental epilepsy using different protocols and miRNA profiling performed. Most of the recent studies reviewed had performed miRNA profiling in hippocampal tissues and a large number of microRNAs were dysregulated when compared to controls. Most notably, miR-132-3p, -146a-5p, -10a-5p, -21a-3p, -27a-3p, -142a-5p, -212-3p, -431-5p, and -155 were upregulated in both the mouse and rat studies. Overexpression of miR-137 and miR-219 decreased seizure severity in a mouse epileptic model, and suppression of miR-451, -10a-5p, -21a-5p, -27a-5p, -142a-5p, -431-5p, -155, and -134 had a positive influence on seizure behavior. In the rat studies, overexpression of miR-139-5p decreased neuronal damage in drug-resistant rats and inhibition of miR-129-2-3p, -27a-3p, -155, -134, -181a, and -146a had a positive effect on seizure behavior and/or reduced the loss of neuronal cells. Further studies are warranted using adult female and immature male and female animals. It would also be helpful to test the ability of specific agomirs and antagomirs to control seizure activity in a subhuman primate model of epilepsy such as adult marmosets injected intraperitoneally with pilocarpine or cynomolgus monkeys given intrahippocampal injections of kainic acid.

MicroRNAs as biomarkers in glaucoma and potential therapeutic targets.

Glaucoma is a neurodegenerative disease in which optic nerve damage and visual field defects occur. It is a leading cause of irreversible blindness. Its pathogenesis is largely unknown although several risk factors have been identified, with an increase in intraocular pressure being the main one. Lowering of intraocular pressure is the only treatment available. Open-angle glaucoma is the most common form of the condition, accounting for ~90% of all cases of glaucoma, with primary open-angle glaucoma and exfoliation glaucoma being the most frequent types. There are strong indications that microRNAs play important roles in the pathogenesis of primary open-angle glaucoma. Most of the recent studies reviewed had performed microRNA profiling in aqueous humor from glaucoma patients compared to controls who were chiefly cataract patients. A very large number of microRNAs were dysregulated but with limited overlap between individual studies. MiRNAs in aqueous humor that could be possible targets for therapeutic intervention are miR-143-3p, miR-125b-5p, and miR-1260b. No overlap of findings occurred within the dysregulated miRNAs for blood plasma, blood serum, peripheral blood mononuclear cells, and tears of primary open-angle glaucoma patients. Several important limitations were identified in these studies. Further studies are warranted of microRNA expression in aqueous humor and blood samples of primary open-angle glaucoma patients in the early stages of the disease so that validated biomarkers can be identified and treatment initiated. In addition, whether modifying the levels of specific microRNAs in aqueous humor or tears has a beneficial effect on intraocular pressure and ophthalmic examination of the eyes should be investigated using suitable animal models of glaucoma.

Biomaterial and tissue-engineering strategies for the treatment of brain neurodegeneration.

The incidence of neurodegenerative diseases is increasing due to changing age demographics and the incidence of sports-related traumatic brain injury is tending to increase over time. Currently approved medicines for neurodegenerative diseases only temporarily reduce the symptoms but cannot cure or delay disease progression. Cell transplantation strategies offer an alternative approach to facilitating central nervous system repair, but efficacy is limited by low in vivo survival rates of cells that are injected in suspension. Transplanting cells that are attached to or encapsulated within a suitable biomaterial construct has the advantage of enhancing cell survival in vivo. A variety of biomaterials have been used to make constructs in different types that included nanoparticles, nanotubes, microspheres, microscale fibrous scaffolds, as well as scaffolds made of gels and in the form of micro-columns. Among these, Tween 80-methoxy poly(ethylene glycol)-poly(lactic-co-glycolic acid) nanoparticles loaded with rhynchophylline had higher transport across a blood-brain barrier model and decreased cell death in an in vitro model of Alzheimer's disease than rhynchophylline or untreated nanoparticles with rhynchophylline. In an in vitro model of Parkinson's disease, trans-activating transcriptor bioconjugated with zwitterionic polymer poly(2-methacryoyloxyethyl phosphorylcholine) and protein-based nanoparticles loaded with non-Fe hemin had a similar protective ability as free non-Fe hemin. A positive effect on neuron survival in several in vivo models of Parkinson's disease was associated with the use of biomaterial constructs such as trans-activating transcriptor bioconjugated with zwitterionic polymer poly(2-methacryoyloxyethyl phosphorylcholine) and protein-based nanoparticles loaded with non-Fe hemin, carbon nanotubes with olfactory bulb stem cells, poly(lactic-co-glycolic acid) microspheres with attached DI-MIAMI cells, ventral midbrain neurons mixed with short fibers of poly-(L-lactic acid) scaffolds and reacted with xyloglucan with/without glial-derived neurotrophic factor, ventral midbrain neurons mixed with Fmoc-DIKVAV hydrogel with/without glial-derived neurotrophic factor. Further studies with in vivo models of Alzheimer's disease and Parkinson's disease are warranted especially using transplantation of cells in agarose micro-columns with an inner lumen filled with an appropriate extracellular matrix material.

MicroRNA expression in animal models of amyotrophic lateral sclerosis and potential therapeutic approaches.

A review of recent animal models of amyotrophic lateral sclerosis showed a large number of miRNAs had altered levels of expression in the brain and spinal cord, motor neurons of spinal cord and brainstem, and hypoglossal, facial, and red motor nuclei and were mostly upregulated. Among the miRNAs found to be upregulated in two of the studies were miR-21, miR-155, miR-125b, miR-146a, miR-124, miR-9, and miR-19b, while those downregulated in two of the studies included miR-146a, miR-29, miR-9, and miR-125b. A change of direction in miRNA expression occurred in some tissues when compared (e.g., miR-29b-3p in cerebellum and spinal cord of wobbler mice at 40 days), or at different disease stages (e.g., miR-200a in spinal cord of SOD1(G93A) mice at 95 days vs. 108 and 112 days). In the animal models, suppression of miR-129-5p resulted in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and tended to improve motor neuron survival in the SOD1(G93A) mouse model. Suppression of miR-155 was also associated with increased lifespan, while lowering of miR-29a tended to improve lifespan in males and increase muscle strength in SOD1(G93A) mice. Overexpression of members of miR-17~92 cluster improved motor neuron survival in SOD1(G93A) mice. Treatment with an artificial miRNA designed to target hSOD1 increased lifespan and improved muscle strength in SOD1(G93A) animals. Further studies with animal models of amyotrophic lateral sclerosis are warranted to validate these findings and identify specific miRNAs whose suppression or directed against hSOD1 results in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and improved motor neuron survival in SOD1(G93A) animals.

MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis.

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes. Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia. Frontotemporal dementia is characterized by progressive impairments in behavior, executive function, and language. There are two main clinical subtypes: behavioral-variant frontotemporal dementia and primary progressive aphasia. The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients. Without validated biomarkers, the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features, but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders. In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies. Measurement of specific miRNAs singly or in combination, or as miRNA pairs (as a ratio) in blood plasma, serum, or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls, Alzheimer's disease, and amyotrophic lateral sclerosis. Furthermore, upregulation of miR-223-3p and downregulation of miR-15a-5p, which occurred both in blood serum and cerebrospinal fluid, distinguished behavioral-variant frontotemporal dementia from healthy controls. Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia, respectively, from healthy controls. Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p, miR-15a-5p, miR-22-3p in blood serum and cerebrospinal fluid, and miR-124 in cerebrospinal fluid. No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes. Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.

Intraperitoneal Administration of Forskolin Reverses Motor Symptoms and Loss of Midbrain Dopamine Neurons in PINK1 Knockout Rats.

BACKGROUND: Parkinson's disease (PD) is a relentless, chronic neurodegenerative disease characterized by the progressive loss of substantia nigra (SN) neurons that leads to the onset of motor and non-motor symptoms. Standard of care for PD consists of replenishing the loss of dopamine through oral administration of Levodopa; however, this treatment is not disease-modifying and often induces intolerable side effects. While the etiology that contributes to PD is largely unknown, emerging evidence in animal models suggests that a significant reduction in neuroprotective Protein Kinase A (PKA) signaling in the SN contributes to PD pathogenesis, suggesting that restoring PKA signaling in the midbrain may be a new anti-PD therapeutic alternative. OBJECTIVE: We surmised that pharmacological activation of PKA via intraperitoneal administration of Forskolin exerts anti-PD effects in symptomatic PTEN-induced kinase 1 knockout (PINK1-KO), a bona fide in vivo model of PD. METHODS: By using a beam balance and a grip strength analyzer, we show that Forskolin reverses motor symptoms and loss of hindlimb strength with long-lasting therapeutic effects (> 5 weeks) following the last dose. RESULTS: In comparison, intraperitoneal treatment with Levodopa temporarily (24 h) reduces motor symptoms but unable to restore hindlimb strength in PINK1-KO rats. By using immunohistochemistry and an XF24e BioAnalyzer, Forskolin treatment reverses SN neurons loss, elevates brain energy production and restores PKA activity in SN in symptomatic PINK1-KO rats. CONCLUSION: Overall, our collective in vivo data suggest that Forskolin is a promising disease-modifying therapeutic alternative for PD and is superior to Levodopa because it confers long-lasting therapeutic effects.

MicroRNAs as diagnostic and prognostic biomarkers of age-related macular degeneration: advances and limitations.

A main cause of vision loss in the elderly is age-related macular degeneration (AMD). Among the cellular, biochemical, and molecular changes linked to this disease, inflammation and angiogenesis appear as being crucial in AMD pathogenesis and progression. There are two forms of the disease: dry AMD, accounting for 80-90% of cases, and wet AMD. The disease usually begins as dry AMD associated with retinal pigment epithelium and photoreceptor degeneration, whereas wet AMD is associated with choroidal neovascularization resulting in severe vision impairment. The new vessels are largely malformed, leading to blood and fluid leakage within the disrupted tissue, which provokes inflammation and scar formation and results in retinal damage and detachment. MicroRNAs are dysregulated in AMD and may facilitate the early detection of the disease and monitoring disease progression. Two recent reviews of microRNAs in AMD had indicated weaknesses or limitations in four earlier investigations. Studies in the last three years have shown considerable progress in overcoming some of these concerns and identifying specific microRNAs as biomarkers for AMD. Further large-scale studies are warranted using appropriate statistical methods to take into account gender and age disparity in the study populations and confounding factors such as smoking status.

Altered microRNA expression in animal models of Huntington's disease and potential therapeutic strategies.

A review of recent animal models of Huntington's disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex, and which were mostly downregulated. Among the altered microRNAs were miR-9/9*, miR-29b, miR-124a, miR-132, miR-128, miR-139, miR-122, miR-138, miR-23b, miR-135b, miR-181 (all downregulated) and miR-448 (upregulated), and similar changes had been previously found in Huntington's disease patients. In the animal cell studies, the altered microRNAs included miR-9, miR-9*, miR-135b, miR-222 (all downregulated) and miR-214 (upregulated). In the animal models, overexpression of miR-155 and miR-196a caused a decrease in mutant huntingtin mRNA and protein level, lowered the mutant huntingtin aggregates in striatum and cortex, and improved performance in behavioral tests. Improved performance in behavioral tests also occurred with overexpression of miR-132 and miR-124. In the animal cell models, overexpression of miR-22 increased the viability of rat primary cortical and striatal neurons infected with mutant huntingtin and decreased huntingtin -enriched foci of ≥ 2 µm. Also, overexpression of miR-22 enhanced the survival of rat primary striatal neurons treated with 3-nitropropionic acid. Exogenous expression of miR-214, miR-146a, miR-150, and miR-125b decreased endogenous expression of huntingtin mRNA and protein in HdhQ111/HdhQ111 cells. Further studies with animal models of Huntington's disease are warranted to validate these findings and identify specific microRNAs whose overexpression inhibits the production of mutant huntingtin protein and other harmful processes and may provide a more effective means of treating Huntington's disease in patients and slowing its progression.