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MicroRNA Dysregulation in Alzheimer's Disease

Putteeraj M, Fairuz YM, Teoh SL

CNS Neurol Disord Drug Targets, 2017;16(9):1000-1009.
PMID: 28782488 DOI: 10.2174/1871527316666170807142311

BACKGROUND AND OBJECTIVE: Alzheimer's disease (AD) is arguably the largest healthcare issue of our time. AD is thought to be principally the result of an inter-play between the β-amyloid peptide and Tau, and it is driven by several genetic and environmental risk factors. Recent studies have shown that small non-protein-coding microRNA (miRNA) and the associated post-transcriptional gene regulation are important regulators of many neurodegenerative diseases, including AD. We reviewed recent studies identifying various miRNA dysregulated in AD. These miRNAs could play a significant role in the pathophysiology of AD, in both β-amyloid peptide and Tau toxicity.
CONCLUSION: The identification of dysregulated miRNAs pattern can serve as specific AD biomarkers which may provide the basis for new and effective diagnostic approach. In addition, these miRNAs may represent new targets for pharmaceutical development.
Early-life citalopram-induced impairments in sexual behavior and the role of androgen receptor

Soga T, Wong DW, Putteeraj M, Song KP, Parhar IS

Neuroscience, 2012 Dec 6;225:172-84.
PMID: 22960312 DOI: 10.1016/j.neuroscience.2012.08.061

Postnatal treatment with selective serotonin reuptake inhibitors (SSRIs) has been found to affect brain development and the regulation of reproduction in rodent models. The normal masculinization process in the brain requires a transient decrease in serotonin (5-HT) levels in the brain during the second postnatal week. Strict regulation of androgen receptor (AR) and gonadotropin-releasing hormone (GnRH) expression is important to control male reproductive activity. Therefore, this study was designed to examine the effects of a potent SSRI (citalopram) on male sexual behavior and expression levels of AR and GnRH in adult male mice receiving either vehicle or citalopram (10mg/kg) daily during postnatal days 8-21. The citalopram-treated male mice showed altered sexual behavior, specifically a significant reduction in the number of intromissions preceding ejaculation compared with the vehicle-treated mice. The citalopram-treated male mice displayed elevated anxiety-like behavior in an open field test and lower locomotor activity in their home cage during the subjective night. Although there was no change in GnRH and AR mRNA levels in the preoptic area (POA), quantified by real-time polymerase chain reaction, immunostained AR cell numbers in the medial POA were decreased in the citalopram-treated male mice. These results suggest that the early-life inhibition of 5-HT transporters alters the regulation of AR expression in the medial POA, likely causing decreased sexual behavior and altered home cage activity in the subjective night.
Fulltext A "Timed" Kiss Is Essential for Reproduction: Lessons from Mammalian Studies

Putteeraj M, Soga T, Ubuka T, Parhar IS

Front Endocrinol (Lausanne), 2016;7:121.
PMID: 27630616 DOI: 10.3389/fendo.2016.00121

Reproduction is associated with the circadian system, primarily as a result of the connectivity between the biological clock in the suprachiasmatic nucleus (SCN) and reproduction-regulating brain regions, such as preoptic area (POA), anteroventral periventricular nucleus (AVPV), and arcuate nucleus (ARC). Networking of the central pacemaker to these hypothalamic brain regions is partly represented by close fiber appositions to specialized neurons, such as kisspeptin and gonadotropin-releasing hormone (GnRH) neurons; accounting for rhythmic release of gonadotropins and sex steroids. Numerous studies have attempted to dissect the neurochemical properties of GnRH neurons, which possess intrinsic oscillatory features through the presence of clock genes to regulate the pulsatile and circadian secretion. However, less attention has been given to kisspeptin, the upstream regulator of GnRH and a potent mediator of reproductive functions including puberty. Kisspeptin exerts its stimulatory effects on GnRH secretion via its cognate Kiss-1R receptor that is co-expressed on GnRH neurons. Emerging studies have found that kisspeptin neurons oscillate on a circadian basis and that these neurons also express clock genes that are thought to regulate its rhythmic activities. Based on the fiber networks between the SCN and reproductive nuclei such as the POA, AVPV, and ARC, it is suggested that interactions among the central biological clock and reproductive neurons ensure optimal reproductive functionality. Within this neuronal circuitry, kisspeptin neuronal system is likely to "time" reproduction in a long term during development and aging, in a medium term to regulate circadian or estrus cycle, and in a short term to regulate pulsatile GnRH secretion.
Flavonoids and its Neuroprotective Effects on Brain Ischemia and Neurodegenerative Diseases

Putteeraj M, Lim WL, Teoh SL, Yahaya MF

Curr Drug Targets, 2018;19(14):1710-1720.
PMID: 29577854 DOI: 10.2174/1389450119666180326125252

Brain ischemia is among the leading cause of death with majority of the cases are associated with ischemic strokes. It can occur in two forms of either focal or global ischemia. Neurodegenerative disorder such as Alzheimer and Parkinson diseases is also on the rise worldwide. These disorders have common similarities; i.e. they all affecting the central nervous system with debilitating effect to the patient. In this review, we look into the promising role of flavonoids, a natural bioactive compound found abundant in vegetables, fruits and traditional herbs. Treatment with flavonoids such as curcumin, lycopene, ginsenoside, vitexin and baicalin have shown promising neuroprotective effects against ischemic-induced injury. Besides anticancer, antioxidant and immunomodulation properties, flavonoid also exerts neuroprotective effects by increases neuronal viability, increases tissue perfusion and cerebral blood flow and reduce ischemic-related apoptosis. In addition, flavonoid also exerts anti-amyloidogenic effect and reduces loss of dopaminergic neurons in the brain. These results suggesting flavonoids might be able to serve as a potential therapeutic agent in brain disorders.