Telmisartan Protects Mitochondrial Function, Gait, and Neuronal Apoptosis by Activating the Akt/GSK3ß/PGC1α Pathway in an MPTP-Induced Mouse Model of Parkinson's Disease.

BACKGROUND: Mitochondrial dysfunction is one of the major hallmarks of Parkinson's disease (PD). Recently, angiotensin II type 1 and type 2 receptors (AT1R, AT2R) were reported to be present on the mitochondrial membrane. Both are crucial players in the brain renin-angiotensin system (RAS). Current evidence indicates that blockade of brain AT1R protects dopaminergic neurons in PD. METHODS: Thus, the current study was aimed to explore the effects of Telmisartan (Tel), a selective AT1R blocker, on mitochondrial function and a mouse model by exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [250 mg/kg body weight (10 divided i.p. injections, each 25 mg/kg body weight at 3.5 days interval) + Probenecid 250 mg/kg]. Gait function was assessed by beam walk, and mice were euthanized on the 35th day and their brain tissues isolated for Western blot analysis. RESULTS: Pretreatment with Tel significantly protected motor functions during the beam walk in MPTP-treated mice. Tel attenuated the increased levels of AT1R, α-syn, and inflammatory markers such as inducible nitric oxide synthase (iNOS) and ionized calcium-binding adaptor molecule 1 (IBA1) in MPTP-treated mice. In addition, Tel preserved the expression of AT2R, tyrosine hydroxylase (TH), p-Akt/Akt, and p-GSK3ß (Ser-9)/GSK3ß, as well as protecting mitofusin protein 1 (MFN1) and Peroxisome proliferator-activated receptor-gamma coactivator-α (PGC1α), a critical activator of mitochondrial biogenesis. CONCLUSION: These results indicate that Tel protects mitochondrial function and gait in a mouse model of PD by modulating the Akt/GSK3ß/PGC1α pathway.

Effects of Telmisartan, an AT1 receptor antagonist, on mitochondria-specific genes expression in a mouse MPTP model of Parkinsonism.

Background: Mitochondrial dysfunction plays a crucial role in Parkinson's disease (PD) pathogenesis. The present study was undertaken to investigate the effects of Telmisartan (TEL), an angiotensin II type 1 receptor (AT1R) blocker, on the mitochondria-specific genes expression in a mouse model of Parkinsonism. Materials and methods: Mice were divided into 5 groups with 6 in each; Group I received 0.5% CMC (control) + saline, Group II received 0.5% CMC + 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (positive control), Group III & IV received MPTP + TEL 3 and 10 mg/kg, p.o. respectively, Group V received TEL 10 mg/kg, p.o. (drug control). MPTP was given 80 mg/kg intraperitoneal in two divided doses (40 mg/kg × 2 at 16 h time interval). Vehicle or TEL was administered 1 h before the MPTP injection. Motor function was assessed 48 h after the first dose of MPTP and animals were euthanized to collect brain. Results: Mice intoxicated with MPTP showed locomotor deficits and significant upregulation of α-synuclein (α-syn), downregulation of metastasis-associated protein 1 (MTA1), and Ubiquitin C-terminal hydrolase L1 (UCHL1) in the substantia nigra pars compacta (SNpc) and Striatum (STr) regions of brains. In addition, MPTP intoxication down-regulated mitochondria-specific genes such as DJ-1, PTEN-induced putative kinase 1 (PINK1), Parkin, enriched with leucine repeats kinase 2 (LRRK2) gene expfression. Pre-treatment with TEL restored locomotor functions and upregulated PINK1, Parkin, LRRK2, DJ-1, MTA1 and UCHL1. Conclusion: The present study evidences that TEL has the ability to improve mitochondrial functions in PD.

Mitochondrial and Organellar Crosstalk in Parkinson's Disease.

Mitochondrial dysfunction is a well-established pathological event in Parkinson's disease (PD). Proteins misfolding and its impaired cellular clearance due to altered autophagy/mitophagy/pexophagy contribute to PD progression. It has been shown that mitochondria have contact sites with endoplasmic reticulum (ER), peroxisomes and lysosomes that are involved in regulating various physiological processes. In pathological conditions, the crosstalk at the contact sites initiates alterations in intracellular vesicular transport, calcium homeostasis and causes activation of proteases, protein misfolding and impairment of autophagy. Apart from the well-reported molecular changes like mitochondrial dysfunction, impaired autophagy/mitophagy and oxidative stress in PD, here we have summarized the recent scientific reports to provide the mechanistic insights on the altered communications between ER, peroxisomes, and lysosomes at mitochondrial contact sites. Furthermore, the manuscript elaborates on the contributions of mitochondrial contact sites and organelles dysfunction to the pathogenesis of PD and suggests potential therapeutic targets.

Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders.

Phosphodiesterases (PDE) are a diverse family of enzymes (11 isoforms so far identified) responsible for the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which are involved in several cellular and biochemical functions. Phosphodiesterase 4 (PDE4) is the major isoform within this group and is highly expressed in the mammalian brain. An inverse association between PDE4 and cAMP levels is the key mechanism in various pathophysiological conditions like airway inflammatory diseases-chronic obstruction pulmonary disease (COPD), asthma, psoriasis, rheumatoid arthritis, and neurological disorders etc. In 2011, roflumilast, a PDE4 inhibitor (PDE4I) was approved for the treatment of COPD. Subsequently, other PDE4 inhibitors (PDE4Is) like apremilast and crisaborole were approved by the Food and Drug Administration (FDA) for psoriasis, atopic dermatitis etc. Due to the adverse effects like unbearable nausea and vomiting, dose intolerance and diarrhoea, PDE4 inhibitors have very less clinical compliance. Efforts are being made to develop allosteric modulation with high specificity to PDE4 isoforms having better efficacy and lesser adverse effects. Interestingly, repositioning PDE4Is towards neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and sleep disorders, is gaining attention. This review is an attempt to summarize the data on the effects of PDE4 overexpression in neurological disorders and the use of PDE4Is and newer allosteric modulators as therapeutic options. We have also compiled a list of on-going clinical trials on PDE4 inhibitors in neurological disorders.

Protein Nutrition in Autism.

Autism is a developmental disorder that affects communication and behavior. Although autism can be diagnosed at any age, it is said to be a "developmental disorder" because symptoms generally appear in the first 2 years of life. The primary cause of autism is still not clear and therapy is currently restricted to controlling behavioral abnormalities. However, emerging studies have shown a link between mitochondrial dysfunction and autism. Dietary supplements that promote mitochondrial biogenesis and inhibit the production of oxidative stress have been used to treat autism patients. Dietary adjustments in treating autism is a novel approach to suppress autistic symptoms. Supplementation with antioxidants has been found to not only inhibit cognitive decline but also improve behavioral symptoms in autism. Dietary supplements fortified with vitamins should only be given under the supervision of a physician. A wide range of nutraceuticals are under clinical trials to understand whether they physiologically target mitochondrial pathways and improve the quality of life in autism.

Autism and Gut-Brain Axis: Role of Probiotics.

Characterized by a wide range of behavioural, social and language problems, autism is a complex developmental disability that affects an individual's capacity to communicate and interact with others. Although the real causes that lead to the development of autism are still unclear, the gastrointestinal tract has been found to play a major role in the development of autism. Alterations in macrobiotic compositions have been reported in autistic children. Irregularities in carbohydrate digestion and absorption could also explain some of the gastrointestinal problems reported in autistic patients, although their role in the neurological and behavioural problems remains uncertain. A relationship between improved gut health and decrease of symptoms in autism has been reported as well. Studies done to evaluate the gluten-free diets, casein-free diets, pre- and probiotic and multivitamin supplementation have shown promising results. Probiotics have been thought to alleviate the progression of autism and reduce cognitive and behavioural deficits.

Dendritic spines: Revisiting the physiological role.

Dendritic spines are small, thin, specialized protrusions from neuronal dendrites, primarily localized in the excitatory synapses. Sophisticated imaging techniques revealed that dendritic spines are complex structures consisting of a dense network of cytoskeletal, transmembrane and scaffolding molecules, and numerous surface receptors. Molecular signaling pathways, mainly Rho and Ras family small GTPases pathways that converge on actin cytoskeleton, regulate the spine morphology and dynamics bi-directionally during synaptic activity. During synaptic plasticity the number and shapes of dendritic spines undergo radical reorganizations. Long-term potentiation (LTP) induction promote spine head enlargement and the formation and stabilization of new spines. Long-term depression (LTD) results in their shrinkage and retraction. Reports indicate increased spine density in the pyramidal neurons of autism and Fragile X syndrome patients and reduced density in the temporal gyrus loci of schizophrenic patients. Post-mortem reports of Alzheimer's brains showed reduced spine number in the hippocampus and cortex. This review highlights the spine morphogenesis process, the activity-dependent structural plasticity and mechanisms by which synaptic activity sculpts the dendritic spines, the structural and functional changes in spines during learning and memory using LTP and LTD processes. It also discusses on spine status in neurodegenerative diseases and the impact of nootropics and neuroprotective agents on the functional restoration of dendritic spines.