Hongwen He

Anti-Amyloidogenic and Anti-Apoptotic Role of Melatonin in Alzheimer Disease

Alzheimer disease (AD) is an age-related neurodegenerative disorder characterized by the presence of senile plaques, neurofibrillary tangles and neuronal loss. Amyloid-β protein (Aβ) deposition plays a critical role in the development of AD. It is now generally accepted that massive neuronal death due to apoptosis is a common characteristic in the brains of patients suffering from neurodegenerative diseases, and apoptotic cell death has been found in neurons and glial cells in AD. Melatonin is a secretory product of the pineal gland; melatonin is a potent antioxidant and free radical scavenger and may play an important role in aging and AD. Melatonin decreases during aging and patients with AD have a more profound reduction of this indoleamine. Additionally, the antioxidant properties, the anti-amyloidogenic properties and anti-apoptotic properties of melatonin in AD models have been studied. In this article, we review the anti-amyloidogenic and anti-apoptotic role of melatonin in AD

Differential effects of melatonin on amyloid‐β peptide 25–35‐induced mitochondrial dysfunction in hippocampal neurons at different stages of culture

Abstract:  β‐Amyloid (Aβ) is strongly involved in the pathogenesis of Alzheimer’s disease (AD), and mitochondria play an important role in neurodegenerative disorders. To determine whether any different effect of melatonin on cultured neurons treated with Aβ in vitro and which may be produced through its different action on mitochondria at different stages of culture, we investigated the damage of cultured rat hippocampal neurons mitochondrial function induced by Aβ in young neurons [days in vitro 10 (DIV 10)] and senescent neurons (DIV 25) and the protective effect of melatonin. Rat hippocampal neurons were incubated with amyloid‐β peptide 25–35 (Aβ25‐35) alone or pretreatment with melatonin. Cell viability, mitochondrial membrane potential (Δψm), ATP and the activity of the respiratory chain complexes were measured. Data showed that Aβ25‐35 caused a reduction in Δψm, inhibited the activity of the respiratory chain complexes and led to ATP depletion, melatonin attenuated Aβ25‐35‐induced mitochondrial impairment in young neurons, whereas melatonin had no effect on Aβ25‐35‐induced mitochondrial damage in senescent neurons. These results demonstrate that melatonin has differential effect on Aβ25‐35‐induced mitochondrial dysfunction at different stages of culture and suggest that melatonin is useful for the prevention of AD, rather than treatment.

Carbon monoxide: A gas that modulates nociception

Carbon monoxide (CO) has been recognized to act as an atypical neurotransmitter or neuromodulator in the nervous system and to be involved in a wide variety of neuronal activities. Several lines of evidence suggest that CO may play a role through multiple mechanisms in nociception processing. Differential regulation of a family of CO‐generating enzymes, heme oxygenase (HO), contributes mainly to the complexity underlying the role of CO in nociception. This Mini‐Review describes the latest evidence for the role of CO during normal sensory transmission and pathological pain conditions and discusses potential cellular mechanisms by which CO is involved in pathological pain.

Melatonin Effects on Hard Tissues: Bone and Tooth

Melatonin is an endogenous hormone rhythmically produced in the pineal gland under the control of the suprachiasmatic nucleus (SCN) and the light/dark cycle. This indole plays an important role in many physiological processes including circadian entrainment, blood pressure regulation, seasonal reproduction, ovarian physiology, immune function, etc. Recently, the investigation and applications of melatonin in the hard tissues bone and tooth have received great attention. Melatonin has been investigated relative to bone remolding, osteoporosis, osseointegration of dental implants and dentine formation. In the present review, we discuss the large body of published evidence and review data of melatonin effects on hard tissues, specifically, bone and tooth.

Melatonin influences proliferation and differentiation of rat dental papilla cells in vitro and dentine formation in vivo by altering mitochondrial activity

Melatonin mediates a variety of biological processes ranging from the control of circadian rhythms to immune regulation. Melatonin also influences bone formation and osteointegration of dental implants. However, the effects of melatonin on dentine formation have not been examined. This study investigated the effects of melatonin on the proliferation and differentiation of rat dental papilla cells (rDPCs) in vitro and dentine formation in vivo. We found that melatonin (0, 10−12, 10−10,10−8 m) induced a dose‐dependent reduction in rDPCs proliferation, increased alkaline phosphatase (ALP) activity, the expression of dentine sialoprotein (DSP), and mineralized matrix formation in vitro. In vivo melatonin (50 mg/kg, BW, i.p.) inhibited dentine formation. Melatonin (10−8 m) suppressed the activity of complex I and IV in the basal medium (OS−) and enhanced the activity of complex I and complex IV in osteogenic medium (OS+). These results demonstrate that melatonin suppresses the proliferation and promotes differentiation of rDPCs, the mechanisms of which may be related to activity of mitochondrial complex I and complex IV.

The role of nitric oxide in orofacial pain

Nitric oxide (NO) is a free radical gas that has been shown to be produced by nitric oxide synthase (NOS) in different cell types and recognized to act as a neurotransmitter or neuromodulator in the nervous system. NOS isoforms are expressed and/or can be induced in the related structures of trigeminal nerve system, in which the regulation of NOS biosynthesis at different levels of gene expression may allow for a fine control of NO production. Several lines of evidence suggest that NO may play a role through multiple mechanisms in orofacial pain processing. This report will review the latest evidence for the role of NO involved in orofacial pain and the potential cellular mechanisms are also discussed.

Expression and colocalization of NADPH-diaphorase and heme oxygenase-2 in trigeminal ganglion and mesencephalic trigeminal nucleus of the rat

Carbon monoxide (CO) and nitric oxide (NO) are two endogenously produced gases that can function as second messenger molecules in the nervous system. The enzyme systems responsible for CO and NO biosynthesis are heme oxygenase (HO) and nitric oxide synthase (NOS), respectively. The present study was undertaken to examine the distribution of HO-2 and NOS of the trigeminal primary afferent neurons of the rat, located in the trigeminal ganglion (TG) and mesencephalic trigeminal nucleus (MTN), using histochemistry and immunohistochemistry. NADPH-d staining was found in most neurons in TG. The intensely NADPH-d-stained neurons were small- or medium-sized, while the large-sized neurons were less intensely stained. Immunocytochemistry for HO-2 revealed that almost all neurons in TG expressed HO-2, but they did not appear cell size-specific pattern. NADPH-d and HO-2 positive neurons appeared the same pattern, which was NADPH-d activity and HO-2 expression progressively declined from the caudal to rostral part of the MTN. A double staining revealed that the colocalization of NADPH-d/HO-2 neurons was 97.3% in TG and 97.6% in MTN. The remarkable parallels between NADPH-d and HO-2 suggest that NO and CO are likely neurotransmitters and mediate the orofacial nociception and sensory feedback of the masticatory reflex arc together.

Involvement of NOS/NO in the development of chronic dental inflammatory pain in rats.

Nitric oxide (NO) is believed to be an important messenger molecule in nociceptive transmission. To assess the possible roles of NO in trigeminal sensory system, we examined the distribution and density of histochemical staining for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), a marker for nitric oxide synthase (NOS), and immunohistochemical staining for c-Fos, a neuronal activity marker, in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (Vc) following pulp exposure (PX) injured rats. The neurons innervating injured tooth in TG were labeled by the retrograde transport of fluoro-gold (FG). Teeth were processed for H&E staining. We found that NADPH-d activity increased significantly in the TG and Vc following PX pretreatment (7-28 days, especially in 21-28 days). Such changes were closely corresponding to the pattern of c-Fos detected by immunocytochemistry. The results demonstrate that PX-induced chronic pulpal inflammation results in significant alterations in the TG cells and in the Vc, and such changes may underlie the observed NADPH-d activity. It suggests that NOS/NO may play an active role in both peripheral and central processing of nociceptive information following chronic tooth inflammation.

The heme oxygenase system and oral diseases.

Oral Diseases (2011) 17, 252-257 Heme oxygenase (HO) system catabolizes heme into three products: carbon monoxide (CO), biliverdin/bilirubin and free iron, which consists of three forms identified to date: the oxidative stress-inducible protein HO-1 and the constitutive isozymes HO-2 and HO-3. HO has been involved in many physiological and pathophysiological processes, ranging from Alzheimers disease to cancer. The interest in HO system by scientists and clinicians involved with the oral and maxillofacial region is fairly recent, and few papers currently cited on HO relate to diseases in this anatomical area. This review will focus on the current understanding of the physiological significance of HO-1 induction and its possible roles in the oral diseases studied to date. The implications for possible therapeutic manipulation of HO are also discussed.

Mitochondrial dysfunction in long-term neuronal cultures mimics changes with aging

Summary Background Aging is a highly complex process that affects various tissues and systems in the body. Senescent changes are relatively more prevalent and severe in the postmitotic cells. Mitochondria play an important role in the aging process. Recently, cell cultures have been widely used as an in vitro model to study aging. The present study was designed to investigate mitochondrial dysfunction associated with aging in a long-term cell culture system. Material/Methods Rat hippocampal neurons were maintained in culture in serum-free medium for 30 days in vitro (DIV). The morphology and development of hippocampal neurons was observed by phase contrast microscope. The levels of cellular senescence were evaluated by cytochemical staining of senescence-associated β-galactosidase (SA-β-Gal) at DIV 5, 10, 15, 20, 25 and 30. In addition, we investigated the changes in mitochondrial membrane potential (Δψm) and intracellular reactive oxygen species (ROS) generation of hippocampal neurons by flow cytometry at different ages. Results The proportion of the senescent cells steadily increased with age in neuron cultures. Δψm decreased gradually with age in long-term culture, while ROS generation increased. Conclusions This study indicates an age-related decrease in mitochondrial function in long-term hippocampal neuronal culture and suggests that DIV 25 neurons could possibly serve as a platform for the future study of anti-aging from the perspective of mitochondrial function.