Jin Jun Luo

Phagocytosis of Microglia in the Central Nervous System Diseases

Microglia, the resident macrophages of the central nervous system, rapidly activate in nearly all kinds of neurological diseases. These activated microglia become highly motile, secreting inflammatory cytokines, migrating to the lesion area, and phagocytosing cell debris or damaged neurons. During the past decades, the secretory property and chemotaxis of microglia have been well-studied, while relatively less attention has been paid to microglial phagocytosis. So far there is no obvious concordance with whether it is beneficial or detrimental in tissue repair. This review focuses on phagocytic phenotype of microglia in neurological diseases such as Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, traumatic brain injury, ischemic and other brain diseases. Microglial morphological characteristics, involved receptors and signaling pathways, distribution variation along with time and space changes, and environmental factors that affecting phagocytic function in each disease are reviewed. Moreover, a comparison of contributions between macrophages from peripheral circulation and the resident microglia to these pathogenic processes will also be discussed.

Uric acid, hyperuricemia and vascular diseases

Uric acid is the product of purine metabolism. It is known that hyperuricemia, defined as high levels of blood uric acid, is the major etiological factor of gout. A number of epidemiological reports have increasingly linked hyperuricemia with cardiovascular and neurological diseases. Studies highlighting the pathogenic mechanisms of uric acid point to an inflammatory response as the primary mechanism for inducing gout and possibly contributing to uric acids vascular effects. Monosodium urate (MSU) crystals induce an inflammatory reaction, which are recognized by toll-like receptors (TLRs). These TLRs then activate NALP3 inflammasome. MSU also triggers neutrophil activation and further produces immune mediators, which lead to a proinflammatory response. In addition, soluble uric acid can also mediate the generation of free radicals and function as a pro-oxidant. This review summarizes the epidemiological studies of hyperuricemia and cardiovascular disease, takes a brief look at hyperuricemia and its role in neurological diseases, and highlights the studies of the advanced pathological mechanisms of uric acid and inflammation.

Irisin-immunoreactivity in neural and non-neural cells of the rodent

Irisin is a recently identified myokine secreted from the muscle in response to exercise. In the rats and mice, immunohistochemical studies with an antiserum against irisin peptide fragment (42-112), revealed that irisin-immunoreactivity (irIRN) was detected in three types of cells; namely, skeletal muscle cells, cardiomyocytes, and Purkinje cells of the cerebellum. Tissue sections processed with irisin antiserum pre-absorbed with the irisin peptide (42-112) (1 μg/ml) showed no immunoreactivity. Cerebellar Purkinje cells were also immunolabeled with an antiserum against fibronectin type II domain containing 5 (FNDC5), the precursor protein of irisin. Double-labeling of cerebellar sections with irisin antiserum and glutamate decarboxylase (GAD) antibody showed that nearly all irIRN Purkinje cells were GAD-positive. Injection of the fluorescence tracer Fluorogold into the vestibular nucleus of the rat medulla retrogradely labeled a population of Purkinje cells, some of which were also irIRN. Our results provide the first evidence of expression of irIRN in the rodent skeletal and cardiac muscle, and in the brain where it is present in GAD-positive Purkinje cells of the cerebellum. Our findings together with reports by others led us to hypothesize a novel neural pathway, which originates from cerebellum Purkinje cells, via several intermediary synapses in the medulla and spinal cord, and regulates adipocyte metabolism.

Hyperhomocysteinemia and Neurologic Disorders: a Review

Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. It has a physiologic role in DNA metabolism via methylation, a process governed by the presentation of folate, and vitamins B6 and B12. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy (eHcy) can be caused by deficiency of either vitamin B12 or folate, or a combination thereof. Certain genetic factors also cause eHcy, such as C667T substitution of the gene encoding methylenetetrahydrofolate reductase. eHcy has been observed in several medical conditions, such as cardiovascular disorders, atherosclerosis, myocardial infarction, stroke, minimal cognitive impairment, dementia, Parkinsons disease, multiple sclerosis, epilepsy, and eclampsia. There is evidence from laboratory and clinical studies that Hcy, and especially eHcy, exerts direct toxic effects on both the vascular and nervous systems. This article provides a review of the current literature on the possible roles of eHcy relevant to various neurologic disorders.

A Double-edged Sword: Uric Acid and Neurological Disorders

Uric Acid (UA), historically considered as a waste of cellular metabolism, has now received increasing attention because it was found to directly participate in the pathogenesis of many human diseases including neurological disorders. On one hand, low levels of UA are detrimental to the neurons because of its induction it impairs antioxidant capacity in the cell. High levels of UA, on the other hand, lead to an inflammatory response contributing to gout or neuroprotection. In this review, we summarize this biphasic function of uric acid and highlight potential therapeutic targets to treat UA-related neurological diseases.

Phoenixin: a novel peptide in rodent sensory ganglia

Phoenixin-14 amide, herein referred to as phoenixin, is a newly identified peptide from the rat brain. Using a previously characterized rabbit polyclonal antiserum against phoenixin, enzyme-immunoassay detected a high level (>4.5 ng/g tissue) of phoenixin-immunoreactivity (irPNX) in the rat spinal cords. Immunohistochemical studies revealed irPNX in networks of cell processes in the superficial dorsal horn, spinal trigeminal tract and nucleus of the solitary tract; and in a population of dorsal root, trigeminal and nodose ganglion cells. The pattern of distribution of irPNX in the superficial layers of the dorsal horn was similar to that of substance P immunoreactivity (irSP). Double-labeling the dorsal root ganglion sections showed that irPNX and irSP express in different populations of ganglion cells. In awake mice, intrathecal injection of phoenixin (1 or 5 μg) did not significantly affect the tail-flick latency as compared to that in animals injected with artificial cerebrospinal fluid (aCSF). Intrathecal administration of phoenixin (0.5, 1.25 or 2.5 μg) significantly reduced the number of writhes elicited by intraperitoneal injection of acetic acid (0.6%, 0.3 ml/30 g) as compared to that in mice injected with aCSF. While not affecting the tail-flick latency, phoenixin antiserum (1:100) injected intrathecally 10 min prior to the intraperitoneal injection of acetic acid significantly increased the number of writhes as compared to mice pre-treated with normal rabbit serum. Intrathecal injection of non-amidated phoenixin (2.5 μg) did not significantly alter the number of writhes evoked by acetic acid. Our result shows that phoenixin is expressed in sensory neurons of the dorsal root, nodose and trigeminal ganglia, the amidated peptide is bioactive, and exogenously administered phoenixin may preferentially suppress visceral as opposed to thermal pain.

Scratching activates microglia in the mouse spinal cord

This study tested the hypothesis that repetitive scratching provoked by two known pruritogens, compound 48/80 and 5′‐guanidinonaltrindole (GNTI), is accompanied by activation of microglial cells in the mouse spinal cord. Immunohistochemical studies revealed that the complement receptor 3, also known as cluster determinant 11b (CD11b), a cell surface marker of microglial cells, was upregulated in the spinal cord 10–30 min after a subcutaneous (s.c.) injection of compound 48/80 (50 μg/100 μl) or GNTI (0.3 mg/kg) to the back of the mouse neck. Numerous intensely labeled CD11b‐immunoreactive (CD11b‐ir) cells, with the appearance of hypertrophic reactive microglia, were distributed throughout the gray and white matter. In contrast, weakly labeled CD11b‐ir cells were distributed in the spinal cord from mice injected with saline. Western blots showed that CD11b expression levels were significantly increased in spinal cords of mice injected s.c. with either pruritogen, reached a peak response in about 30 min, and declined to about the basal level in the ensuing 60 min. In addition, phospho‐p38 (p‐p38) but not p38 levels were upregulated in spinal cords from mice injected with compound 48/80 or GNTI, with a time course parallel to that of CD11b expression. Pretreatment of the mice with nalfurafine (20 µg/kg; s.c.), a κ‐opioid receptor agonist that has been shown to suppress scratching, reduced CD11b and p‐p38 expression induced by either pruritogen. The results demonstrate, for the first time, that scratch behavior induced by the pruritogens GNTI and compound 48/80 is accompanied by a parallel activation of microglial cells in the spinal cord.

A cyclic pain: the pathophysiology and treatment of menstrual migraine.

Catamenial migraine is a headache disorder occurring in reproductive-aged women relevant to menstrual cycles. Catamenial migraine is defined as attacks of migraine that occurs regularly in at least 2 of 3 consecutive menstrual cycles and occurs exclusively on day 1 to 2 of menstruation, but may range from 2 days before (defined as −2) to 3 days after (defined as +3 with the first day of menstruation as day +1). There are 2 subtypes: the pure menstrual migraine and menstrually related migraine. In pure menstrual migraine, there are no aura and no migraine occurring during any other time of the menstrual cycle. In contrast, menstrually related migraine also occurs in 2 of 3 consecutive menstrual cycles, mostly on days 1 and 2 of menstruation, but it may occur outside the menstrual cycle. Catamenial migraine significantly interferes with the quality of life and causes functional disability in most sufferers. The fluctuation of estrogen levels is believed to play a role in the pathogenesis of catamenial migraine. In this review, we discuss estrogen and its direct and indirect pathophysiologic roles in menstrual-related migraine headaches and the available treatment for women. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to discuss the pathophysiology of catamenial migraine, identify the risk factors for catamenial migraine among women, and list the prophylactic and abortive treatments for migraines.

Epilepsy in Elderly

Advance technology and life science significantly prolongs human’s lifespan. The prolonged longevity enables people to enjoy longer life but adversely increases the mortality and morbidity of aging-related disorders which may, in turn, devalue the quality of late life. Of the aging-related neurological conditions, increased incidence and prevalence of convulsive disorders, namely seizures or epilepsies, have been documented in literature. Epilepsy is the third most common neurological condition after dementia and stroke among the elderly. Multiple risk factors cause the elderly to be prone to develop seizures or epilepsies, including advanced aging, stroke, traumatic brain injury, dementia, neurodegenerative diseases, brain tumors, obstructive sleep apnea, and obesity. In this article, we highlight the epidemiology, pathophysiology, and clinical manifestations of elderly seizures.

In Vivo Imaging of Brain Infarct with the Novel Fluorescent Probe PSVue 794 in a Rat Middle Cerebral Artery Occlusion-Reperfusion Model

The utility of PSVue 794 (PS794), a near-infrared fluorescent dye conjugated to a bis[zinc (II)-dipicolylamine] (Zn-DPA) targeting moiety, in imaging brain infarct was assessed in a rat middle cerebral artery occlusion-reperfusion model. Following reperfusion, 1 mM PS794 solution was administered intravenously via a tail vein. Fluorescence images were captured between 6 to 72 hours postinjection using a LI-COR Biosciences Pearl Imaging System. Strong fluorescence signals, which may represent the infarct core, were detected in the right hemisphere, ipsilateral to the injured site, and weaker signals in areas surrounding the core. In ischemia-reperfusion rats injected with a control dye not linked to a targeting agent, fluorescence was distributed diffusely throughout the brain. To address the issue of whether Zn-DPA targets apoptotic/necrotic cells, HT22 mouse hippocampal neurons were cultured in either Dulbeccos Modified Eagles Medium, serum-deprived medium, Hanks Balanced Salt Solution, or L-glutamate (10 mM)-containing medium for up to 33 hours. Cells were then double-labeled with PSVue 480 (Zn-DPA conjugated to fluorescein isothiocyanate) and propidium iodide, which labels necrotic cells. Microscopic examination revealed that PS480 targeted apoptotic and necrotic cells. The result indicates that PS794 is applicable to in vivo imaging of brain infarct and that Zn-DPA selectively targets apoptotic/necrotic cells.