Effects of sub-chronic CRH administration into the hypothalamic paraventricular and central amygdala nuclei in male rats with a focus on food intake biomarkers.

CRH neurons are found in the paraventricular nucleus(PVN) and central amygdala(CeA) nuclei. This study investigated the effects of sub-chronic CRH administration into the PVN and CeA nuclei on food intake biomarkers in rats divided into five groups: control, two shams, and two CRH-PVN and CRH-CeA groups(receiving CRH in nuclei for seven days). The CRH-PVN group had significantly higher cumulative food intake and food intake trends than the CRH-CeA group. The CRH-CeA and CRH-PVN groups exhibited significant increases in food intake during hours 1 and 2, respectively. Moreover, to be time-dependent, food intake is modulated by different brain nuclei. The CRH signaling pathway appeared to be activated later in the PVN than CeA. Both groups exhibited significantly higher leptin levels, the CRH-PVN group exhibited higher ghrelin levels and lower glucose levels. Repetitive administration of CRH into the PVN and CeA significantly reduced body weight differences. CRH administration into the PVN affected both leptin and ghrelin levels, but ghrelin had a greater impact on glucose variations and cumulative food intake than leptin. Finally, CRH administration into the PVN and CeA likely activated the HPA axis, and the CeA had a greater impact on the stress circuit than on food intake behavior.

Neuroglial components of brain lesions may provide new therapeutic strategies for multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune and demyelinating disease of the central nervous system (CNS) which leads to focal demyelinated lesions in the brain and spinal cord. Failure of remyelination contributes to chronic disability in young adults. Characterization of events occurring during the demyelination and remyelination processes and those of which subsequently limit remyelination or contribute to demyelination can provide the possibility of new therapies development for MS. Most of the currently available therapies and investigations modulate immune responses and mediators. Since most therapeutic strategies have unsatisfied outcomes, developing new therapies that enhance brain lesion repair is a priority. A close look at cellular and chemical components of MS lesions will pave the way to a better understanding of lesions pathology and will provide possible opportunities for repair strategies and targeted pharmacotherapy. This review summarizes the lesion components and features, particularly the detrimental elements, and discusses the possibility of suggesting new potential targets as therapies for demyelinating diseases like MS.

Ferroptosis inhibition by deferiprone, attenuates myelin damage and promotes neuroprotection in demyelinated optic nerve.

Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal demyelination in the brain and spinal cord. Studies showed that iron released during the course of myelin breakdown exacerbates tissue damage, which is in agreement with the features of iron-dependent cell death, ferroptosis. Here, we aimed to investigate the possible contribution of ferroptosis in the demyelinated optic nerve, and to explore the effectiveness of ferroptosis inhibitor, deferiprone (DFP), on the extent of demyelination, inflammation and axonal damage. For this purpose, focal demyelination was induced by injection of lysolecithin (LPC), into the optic nerve of male C57BL/6J mice. Afterward, optic nerves were harvested at different time points from as early as 6 h up to 7 days post-LPC injection. Next, to evaluate the effectiveness of DFP two groups of animals received daily intraperitoneal injection of DFP for 3 or 7 continuous days. Vehicle groups received saline. Iron deposition was observed at different time points post-LPC injection from 6 h to 7 days post injection. Examining ferroptosis markers showed a significant reduction in glutathione content along with increased level of malondialdehyde and upregulated ferroptosis marker genes at early time points after injection. Besides, DFP treatment during the inflammatory phase of the model resulted in decreased microgliosis and inflammation. Reduced demyelination, microgliosis and astrogliosis was shown in mice that received DFP for 7 days. Moreover, DFP protected against axonal damage and retinal ganglion cells loss. Our results suggest the possible contribution of ferroptosis pathway in the process of demyelination. The therapeutic strategies targeting iron deposition, e.g. DFP treatment might thus represent a promising therapeutic target for patients with MS.

The Cross Talk between Underlying Mechanisms of Multiple Sclerosis and Epilepsy May Provide New Insights for More Efficient Therapies.

Despite the significant differences in pathological background of neurodegenerative diseases, epileptic seizures are a comorbidity in many disorders such as Huntington disease (HD), Alzheimer's disease (AD), and multiple sclerosis (MS). Regarding the last one, specifically, it has been shown that the risk of developing epilepsy is three to six times higher in patients with MS compared to the general population. In this context, understanding the pathological processes underlying this connection will allow for the targeting of the common and shared pathological pathways involved in both conditions, which may provide a new avenue in the management of neurological disorders. This review provides an outlook of what is known so far about the bidirectional association between epilepsy and MS.

ComparativeStudyofCRHMicroinjections Into PVN and CeA Nuclei on Food Intake, Ghrelin, Leptin, and Glucose Levels in Acute Stressed Rats.

INTRODUCTION: Corticotropin-Releasing Hormone (CRH) is involved in stress and energy homeostasis. On the other hand, CRH receptors also exist within the paraventricular nucleus (PVN) and Central Amygdala (CeA) nuclei. The present study compared the effect of CRH microinjections into PVN and CeA on three consecutive hours and cumulative food intake, internal regulatory factors of food intake, such as serum leptin and ghrelin, as well as blood glucose levels in rats under different acute psychological (Social Stress [SS] and Isolation Stress [IS] group) stresses. METHODS: Sixty-six male Wistar rats were randomly allocated to 11 groups: Control, Sham, CRH-PVN, CRH-CeA, SS, IS, SS-CRH-PVN, SS-CRH-CeA, IS-CRH-PVN, and IS-CRH-CeA groups. The CRH (2 µg/kg in 0.5 µL saline) was injected into PVN and CeA nuclei in rats under everyday, acute social stress and isolation stress conditions. RESULTS: Acute isolation and social stresses did not affect cumulative food intake. Whereas isolation stress led to changes in both leptin and glucose levels, social stress reduced only glucose levels. Cumulative food intake significantly decreased under acute CRH injection into the CeA and particularly into the PVN. Blood glucose significantly reduced in all the groups receiving CRH into their CeA. CONCLUSION: The PVN played a more important role compared to CeA on food intake. These nuclei probably employ different mechanisms for their effects on food intake. Besides, it seems that exogenously CRH injection into the PVN probably had a more anorectic effect than naturally activated CRH by stresses. Acute isolation stress had a greater impact than social stress on leptin level and cumulative food intake. Thus, elevated food intake related to leptin compared to ghrelin and glucose levels in the CRH-PVN group under acute social stress.

Targeting the brain lesions using peptides: A review focused on the possibility of targeted drug delivery to multiple sclerosis lesions.

As described by Jean Martin Charcot in 1868, multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS) which leads to permanent disability in patients. Following CNS insults, astrocytes and microglial cells undergo changes, which lead to scar formation in the site of injury. Owning to the pathophysiology of MS lesions, changes in both cellular and extracellular matrix (ECM) components occur over the progression of disease. In spite of advances in therapeutic approaches, drug delivery to MS lesions appears of great interest with big challenges and limitations. Targeting with peptides is a novel promising approach in the field of drug delivery. Recently peptides have been used for active targeting of different pathological disorders in which specific peptides make targeted accumulation of cargos to enhance local drug concentration at the pathological area, lead to increased therapeutic efficacy and decreased side effects. However, specific approaches for targeting the lesion in MS are still lacking. In this review, we discuss the changes of the ECM components as well as the cellular characteristics of demyelinated lesions and emphasis on opportunities for peptide based targeted drug delivery to highlight the possibility of such approaches for neurodegenerative disease with specific focus on MS.

Effects of Isolation and Social Subchronic Stresses on Food Intake and Levels of Leptin, Ghrelin, and Glucose in Male Rats.

BACKGROUND: Exposure to psychological stresses can be a reason for obesity. Therefore, identifying the effective nutritional mechanisms such as feeding markers is of high necessity for the psychological stress conditions. Hence, the present study investigates the effects of subchronic isolation and social stresses on food intake, body weight differences (BWD), and levels of leptin, ghrelin, and glucose in rats. MATERIALS AND METHODS: Eighteen male rats were randomly allocated into three groups: control (Co), isolation stress (IS), and social stress (SS) groups. Rats were under stresses for 7 days. The food intake (for three continuous hours after 16-18 h of food deprivation), BWD, levels of ghrelin, leptin, and glucose were measured. RESULTS: The results showed that the food intake significantly (P < 0.05) reduced during the 1st h in the SS group compared to the Co group. At the 2nd h, the food intake significantly (P < 0.001 and P < 0.01, respectively) decreased in the IS group compared to the Co and SS groups. The cumulative food intake and body weight were significantly (P < 0.05) reduced in the IS group compared to the Co group. The serum ghrelin level significantly reduced in the IS group compared to the Co group. CONCLUSIONS: The subchronic psychological stresses led to a reduction in food intake by the reduction of serum ghrelin levels. It seems that ghrelin might have a more fundamental role in the food intake with respect to the leptin and glucose levels in subchronic stress condition. Furthermore, the decreased body weight justified the reduction of food intake, particularly in subchronic isolation stress.