SIRT1/PARP-1/NLRP3 cascade as a potential target for niacin neuroprotective effect in lipopolysaccharide-induced depressive-like behavior in mice.

Depression is a serious mood disorder characterized by monoamines deficiency, oxidative stress, neuroinflammation, and cell death. Niacin (vitamin B3 or nicotinic acid, NA), a chief mediator of neuronal development and survival in the central nervous system, exerts neuroprotective effects in several experimental models. AIMS: This study aimed to investigate the effect of NA in lipopolysaccharide (LPS) mouse model of depression exploring its ability to regulate sirtuin1/poly (ADP-ribose) polymerase-1 (PARP-1)/nod-likereceptor protein 3 (NLRP3) signaling. MAIN METHODS: Mice were injected with LPS (500 µg/kg, i.p) every other day alone or concurrently with oral doses of either NA (40 mg/kg/day) or escitalopram (10 mg/kg/day) for 14 days. KEY FINDINGS: Administration of NA resulted in significant attenuation of animals' despair reflected by decreased immobility time in forced swimming test. Moreover, NA induced monoamines upsurge in addition to sirtuin1 activation with subsequent down regulation of PARP-1 in the hippocampus. Further, it diminished nuclear factor-κB (NF-κB) levels and inhibited NLRP3 inflammasome with consequent reduction of caspase-1, interleukin-1ß and tumor necrosis factor-α levels, thus mitigating LPS-induced neuroinflammation. NA also reduced tumor suppressor protein (p53) while elevating brain-derived neurotrophic factor levels. LPS-induced decline in neuronal survival was reversed by NA administration with an obvious increase in the number of intact cells recorded in the histopathological micrographs. SIGNIFICANCE: Accordingly, NA is deemed as a prosperous candidate for depression management via targeting SIRT1/PARP-1 pathway.

Targeting α7-nAChR by galantamine mitigates reserpine-induced fibromyalgia-like symptoms in rats: Involvement of cAMP/PKA, PI3K/AKT, and M1/M2 microglia polarization.

Fibromyalgia (FM) is a pain disorder marked by generalized musculoskeletal pain accompanied by depression, fatigue, and sleep disturbances. Galantamine (Gal) is a positive allosteric modulator of neuronal nicotinic acetylcholine receptors (nAChRs) and a reversible inhibitor of cholinesterase. The current study aimed to explore the therapeutic potential of Gal against reserpine (Res)-induced FM-like condition along with investigating the α7-nAChR's role in Gal-mediated effects. Rats were injected with Res (1 mg/kg/day; sc) for 3 successive days then Gal (5 mg/kg/day; ip) was given alone and with the α7-nAChR blocker methyllycaconitine (3 mg/kg/day; ip), for the subsequent 5 days. Galantamine alleviated Res-induced histopathological changes and monoamines depletion in rats' spinal cord. It also exerted analgesic effect along with ameliorating Res-induced depression and motor-incoordination as confirmed by behavioral tests. Moreover, Gal produced anti-inflammatory effect through modulating AKT1/AKT2 and shifting M1/M2 macrophage polarization. The neuroprotective effects of Gal were mediated through activating cAMP/PKA and PI3K/AKT pathways in α7-nAChR-dependent manner. Thus, Gal can ameliorate Res-induced FM-like symptoms and mitigate the associated monoamines depletion, neuroinflammation, oxidative stress, apoptosis, and neurodegeneration through α7-nAChR stimulation, with the involvement of cAMP/PKA, PI3K/AKT, and M1/M2 macrophage polarization.

Microglia polarization in nociplastic pain: mechanisms and perspectives.

Nociplastic pain is the third classification of pain as described by the International Association for the Study of Pain (IASP), in addition to the neuropathic and nociceptive pain classes. The main pathophysiological mechanism for developing nociplastic pain is central sensitization (CS) in which pain amplification and hypersensitivity occur. Fibromyalgia is the prototypical nociplastic pain disorder, characterized by allodynia and hyperalgesia. Much scientific data suggest that classical activation of microglia in the spinal cord mediates neuroinflammation which plays an essential role in developing CS. In this review article, we discuss the impact of microglia activation and M1/M2 polarization on developing neuroinflammation and nociplastic pain, besides the molecular mechanisms engaged in this process. In addition, we mention the impact of microglial modulators on M1/M2 microglial polarization that offers a novel therapeutic alternative for the management of nociplastic pain disorders. Illustrating the mechanisms underlying microglia activation in central sensitization and nociplastic pain. LPS lipopolysaccharide, TNF-α tumor necrosis factor-α, INF-γ Interferon gamma, ATP adenosine triphosphate, 49 P2Y12/13R purinergic P2Y 12/13 receptor, P2X4/7R purinergic P2X 4/7 receptor, SP Substance P, NK-1R Neurokinin 1 receptor, CCL2 CC motif ligand 2, CCR2 CC motif ligand 2 receptor, CSF-1 colony-stimulating factor 1, CSF-1R colony-stimulating factor 1 receptor, CX3CL1 CX3C motif ligand 1, CX3XR1 CX3C motif ligand 1 receptor, TLR toll-like receptor, MAPK mitogen-activated protein kinases, JNK jun N-terminal kinase, ERK extracellular signal-regulated kinase, iNOS Inducible nitric oxide synthase, IL-1ß interleukin-1ß, IL-6 interleukin-6, BDNF brain-derived neurotrophic factor, GABA γ-Aminobutyric acid, GABAR γ-Aminobutyric acid receptor, NMDAR N-methyl-D-aspartate receptor, AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropi-onic acid receptor, IL-4 interleukin-4, IL-13 interleukin-13, IL-10 interleukin-10, Arg-1 Arginase 1, FGF fibroblast growth factor, GDNF glial cell-derived neurotrophic factor, IGF-1 insulin-like growth factor-1, NGF nerve growth factor, CD Cluster of differentiation.

Aqueous extract of Ceratonia siliqua L. leaves elicits antioxidant, anti-inflammatory, and AChE inhibiting effects in amyloid-ß42-induced cognitive deficit mice: Role of α7-nAChR in modulating Jak2/PI3K/Akt/GSK-3ß/ß-catenin cascade.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder attributed to several etiological factors including cholinergic dysregulation, neuroinflammation, oxidative stress, ß-amyloidogenesis, and tauopathy. This demands the search for multitarget drugs, especially of natural sources owing to their pleiotropic activities and low adverse effects. The present study was conducted to investigate the cognitive-improving potential of Ceratonia siliqua L. (Cs) extract compared with donepezil, an acetylcholinesterase inhibitor, on AD-like pathological alterations induced by single intracerebroventricular amyloid-ß42 (Aß42) injection in mice. Aß42-injected mice were treated with Cs (100 mg/kg/day, po) with or without methyllycaconitine (MLA; 1 mg/kg/day, ip), an α7-nAChR antagonist. Aß42-injected animals demonstrated an elevation of hippocampal Aß42, p-Tau, and acetylcholinesterase. They also showed a decline in phosphorylated levels of Jak2, PI3K, Akt, and GSK-3ß, leading to induction of neuroinflammation and oxidative stress. Noteworthy, Cs improved the histopathological and behavioral variables in addition to mitigating AD hallmarks. It also exerted neuroprotection by reducing NF-κBp65 and TNF-α, while elevating Nrf2 and HO-1, along with stabilizing ß-catenin under the impact of Jak2/PI3K/Akt/GSK-3ß signaling. These beneficial effects of Cs were abrogated by MLA co-administration signifying the α7-nAChR involvement in Cs-mediated effects. Therefore, Cs can ameliorate Aß42-induced neurodegeneration by modulating Jak2/PI3K/Akt/GSK-3ß/ß-catenin axis in an α7-nAChR-dependent manner.

Boosting amygdaloid GABAergic and neurotrophic machinery via dapagliflozin-enhanced LKB1/AMPK signaling in anxious demented rats.

Anxiety is a neuropsychiatric disturbance that is commonly manifested in various dementia forms involving Alzheimer's disease (AD). The mechanisms underlying AD-associated anxiety haven't clearly recognized the role of energy metabolism in anxiety represented by the amygdala's autophagic sensors; liver kinase B1 (LKB1)/adenosine monophosphate kinase (AMPK). Dapagliflozin (DAPA), a SGLT2 inhibitor, acts as an autophagic activator through LKB1 activation in several diseases including AD. Herein, the propitious yet undetected anxiolytic potential of DAPA as an autophagic enhancer was investigated in AD animal model with emphasis on amygdala's GABAergic neurotransmission and brain-derived neurotrophic factor (BDNF). Alzheimer's disease was induced by ovariectomy (OVX) along with seventy-days-D-galactose (D-Gal) administration (150 mg/kg/day, i.p). On the 43rd day of D-Gal injection, OVX/D-Gal-subjected rats received DAPA (1 mg/kg/day, p.o) alone or with dorsomorphin the AMPK inhibitor (DORSO, 25 µg/rat, i.v.). In the amygdala, LKB1/AMPK were activated by DAPA inducing GABAB2 receptor stimulation; an effect that was abrogated by DORSO. Dapagliflozin also replenished the amygdala GABA, NE, and 5-HT levels along with glutamate suppression. Moreover, DAPA triggered BDNF production with consequent activation of its receptor, TrkB through activating GABAB2-related downstream phospholipase C/diacylglycerol/protein kinase C (PLC/DAG/PKC) signaling. This may promote GABAA expression, verifying the crosstalk between GABAA and GABAB2. The DAPA's anxiolytic effect was visualized by improved behavioral traits in elevated plus maze together with amendment of amygdala' histopathological abnormalities. Thus, the present study highlighted DAPA's anxiolytic effect which was attributed to GABAB2 activation and its function to induce BDNF/TrkB and GABAA expression through PLC/DAG/PKC pathway in AMPK-dependent manner.

Niacin mitigates blood-brain barrier tight junctional proteins dysregulation and cerebral inflammation in ketamine rat model of psychosis: Role of GPR109A receptor.

Dysregulated inflammatory responses and blood-brain barrier (BBB) dysfunction are recognized as central factors in the development of psychiatric disorders. The present study was designed to evaluate the effect of niacin on BBB integrity in ketamine-induced model of psychosis. Meanwhile, mepenzolate bromide (MPN), a GPR109A receptor blocker, was used to investigate the role of this receptor on the observed niacin's effect. Male Wistar rats received ketamine (30 mg/kg/day, i.p) for 5 consecutive days and then niacin (40 mg/kg/day, p.o), with or without MPN (5 mg/kg/day, i.p), was given for the subsequent 15 days. Three days before the end of experiment, rats were behaviorally tested using open field, novel object recognition, social interaction, and forced swimming tests. Niacin significantly ameliorated ketamine-induced behavioral deficits, amended gamma aminobutyric acid and glutamate concentration, decreased tumor necrosis factor-α and matrix metallopeptidase 9 levels, and increased netrin-1 contents in the hippocampus of rats. Niacin also augmented the hippocampal expression of ZO-1, occludin, and claudin-5 proteins, indicating the ability of niacin to restore the BBB integrity. Moreover, the histopathologic changes in hippocampal neurons were alleviated. Since all the beneficial effects of niacin in the present investigation were partially abolished by the co-administration of MPN; GPR109A receptor was proven to partially mediate the observed antipsychotic effects of niacin. These data revealed that GPR109A-mediated signaling pathways might represent potential targets for therapeutic interventions to prevent or slow the progression of psychosis.

Diapocynin neuroprotective effects in 3-nitropropionic acid Huntington's disease model in rats: emphasis on Sirt1/Nrf2 signaling pathway.

BACKGROUND AND AIM: Huntington's disease (HD) is a rare inherited disease portrayed with marked cognitive and motor decline owing to extensive neurodegeneration. NADPH oxidase is considered as an important contributor to the oxidative injury in several neurodegenerative disorders including HD. Thus, the present study explored the possible neuroprotective effects of diapocynin, a specific NADPH oxidase inhibitor, against 3-nitropropionic acid (3-NP) model of HD in rats. METHODS: Animals received diapocynin (10 mg/kg/day, p.o), 30 min before 3-NP (10 mg/kg/day, i.p) over a period of 14 days. RESULTS: Diapocynin administration attenuated 3-NP-induced oxidative stress with significant increase in reduced glutathione, glutathione-S-transferase, nuclear factor erythroid 2-related factor 2, and brain-derived neurotrophic factor striatal contents contrary to NADPH oxidase (NOX2; gp91phox subunit) diminished expression. Moreover, diapocynin mitigated 3-NP-associated neuroinflammation and glial activation with prominent downregulation of nuclear factor-Ðšß p65 and marked decrement of inducible nitric oxide synthase content in addition to decreased immunoreactivity of ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein; markers of microglial and astroglial activation, respectively. Treatment with diapocynin hindered 3-NP-induced apoptosis with prominent decrease in tumor suppressor protein and Bcl-2-associated X protein contents whereas the anti-apoptotic marker; B-cell lymphoma-2 content was noticeably increased. Diapocynin neuroprotective effects could be attributed to silent information regulator 1 upregulation which curbed 3-NP-associated hazards resulting in improved motor functions witnessed during open field, rotarod, and grip strength tests as well as attenuated 3-NP-associated histopathological derangements. CONCLUSION: The present findings indicated that diapocynin could serve as an auspicious nominee for HD management.

Telmisartan neuroprotective effects in 3-nitropropionic acid Huntington's disease model in rats: Cross talk between PPAR-γ and PI3K/Akt/GSK-3ß pathway.

Huntington's disease (HD) is an inherited devastating neurodegenerative disorder with disabling motor and cognitive derangements that hinder the patients from performing their daily activities. AIMS: The present study was carried out to investigate telmisartan-induced neuroprotection against 3-nitropropionic acid (3-NP) model of HD in rats. MAIN METHODS: Telmisartan was administered orally with a dose of 10 mg/kg/day, 1 h prior to 3-NP (10 mg/kg/day, i.p) for 14 days. KEY FINDINGS: 3-NP-injected animals which were treated with telmisartan showed marked improvement in muscle strength and motor functions evaluated by rotarod, grip strength, and open field tests. Moreover, administration of telmisartan attenuated 3-NP-induced oxidative stress, neuro-inflammation, and apoptosis with prominent decline in malondialdehyde striatal content in addition to NADPH oxidase reduced expression contrary to noticeable increment in reduced glutathione content. Additionally, the pro-inflammatory markers; tumor necrosis factor-α, interleukin-1ß, prostaglandin E2, and cyclooxygenase-2 contents were significantly reduced along with decreased active caspase-3 immunoreactivity. Telmisartan was also implicated in the modulation of phosphatidyl inositol 3-kinase/protein kinase B/glycogen synthase kinase-3ß (PI3K/Akt/GSK-3ß) and extracellular signal-regulated kinase (ERK) 1/2 cascades with consequent anti-oxidative, anti-inflammatory, and anti-apoptotic effects. Photomicrographs of telmisartan-treated animals confirmed its neuroprotective effects showing dismounted neuronal death and obvious increase in neuronal survival. These beneficial effects could be attributed to telmisartan's ability to induce peroxisome proliferator activated receptor-γ expression as well as its well-known blocking effect of angiotensin-II receptors type 1. SIGNIFICANCE: Subsequently, telmisartan is deemed as a promising candidate for HD management.

Cognitive enhancing effect of diapocynin in D-galactose-ovariectomy-induced Alzheimer's-like disease in rats: Role of ERK, GSK-3ß, and JNK signaling.

NADPH oxidase (NOX) has been identified as a crucial contender of oxidative damage in Alzheimer's disease (AD). However, the capability of diapocynin, a NOX inhibitor, to offer neuroprotection in AD models is still a matter of debate. Hence, the current work is dedicated to investigate the influence of diapocynin on cognitive impairment prompted by ovariectomy combined with D-galactose injection in rats (an AD animal model), and to elucidate the signaling mechanisms regulating diapocynin-induced effects. Female rats were exposed to ovariectomy or sham operation. Ovariectomized rats were injected intraperitoneally with D-galactose (150 mg/kg/day) for 70 days and, on day 43, they were orally treated with diapocynin (10 mg/kg/day) for 28 days. Diapocynin amended cognitive functions as confirmed using novel object recognition and Morris water maze tests along with histopathological improvement. It caused a prominent decrement in ß-secretase, p-tau, and amyloid ß, contrary to α-secretase elevation in hippocampus and hampered neuroinflammation and oxidative stress, manifested by declined levels of NOX1, tumor necrosis factor-α, and nuclear factor-kappa B p65. In addition, diapocynin augmented synaptophysin, brain-derived neurotrophic factor, and phospho-cAMP response element binding protein and enhanced protein expression of phosphorylated forms of phosphoinositide 3-kinase (PI3K), glycogen synthase kinase-3ß (GSK-3ß), protein kinase B (Akt), extracellular signal-regulated kinase (ERK) 1/2, ERK kinase kinase (Raf-1), and ERK kinase (MEK) 1/2, while inhibiting those of c-Jun and c-Jun N-terminal kinase (JNK). In conclusion, diapocynin attenuated memory impairment and AD-like anomalies via activating Raf-1/MEK/ERK and PI3K/Akt/GSK-3ß, while inhibiting JNK/c-Jun signaling cascades.

Escitalopram Ameliorates Cognitive Impairment in D-Galactose-Injected Ovariectomized Rats: Modulation of JNK, GSK-3ß, and ERK Signalling Pathways.

Though selective serotonin reuptake inhibitors (SSRIs) have been found to increase cognitive performance in some studies on patients and animal models of Alzheimer's disease (AD), other studies have reported contradictory results, and the mechanism of action has not been fully described. This study aimed to examine the effect of escitalopram, an SSRI, in an experimental model of AD and to determine the involved intracellular signalling pathways. Ovariectomized rats were administered D-galactose (150 mg/kg/day, i.p) over ten weeks to induce AD. Treatment with escitalopram (10 mg/kg/day, p.o) for four weeks, starting from the 7th week of D-galactose injection, enhanced memory performance and attenuated associated histopathological changes. Escitalopram reduced hippocampal amyloid ß 42, ß-secretase, and p-tau, while increasing α-secretase levels. Furthermore, it decreased tumor necrosis factor-α, nuclear factor-kappa B p65, and NADPH oxidase, while enhancing brain-derived neurotrophic factor, phospho-cAMP response element binding protein, and synaptophysin levels. Moreover, escitalopram diminished the protein expression of the phosphorylated forms of c-Jun N-terminal kinase (JNK)/c-Jun, while increasing those of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase-3ß (GSK-3ß), extracellular signal-regulated kinase (ERK) and its upstream kinases MEK and Raf-1. In conclusion, escitalopram ameliorated D-galactose/ovariectomy-induced AD-like features through modulation of PI3K/Akt/GSK-3ß, Raf-1/MEK/ERK, and JNK/c-Jun pathways.

17ß-Estradiol augments antidepressant efficacy of escitalopram in ovariectomized rats: Neuroprotective and serotonin reuptake transporter modulatory effects.

The prevalence or recurrence of depression is seriously increased in women during the transition to and after menopause. The chronic hypo-estrogenic state of menopause may reduce the response to antidepressants; however the influence of estrogen therapy on their efficacy is still controversial. This study aimed at investigating the effects of combining escitalopram with 17ß-estradiol on depression and cognitive impairment induced by ovariectomy, an experimental model of human menopause. Young adult female Wistar rats were subjected to either sham operation or ovariectomy. Ovariectomized animals were treated chronically with escitalopram (10mg/kg/day, i.p) alone or with four doses of 17ß-estradiol (40µg/kg, s.c) given prior to the behavioral tests. Co-administration of 17ß-estradiol improved escitalopram-induced antidepressant effect in forced swimming test verified as more prominent decrease in the immobility time without opposing its memory enhancing effect in Morris water maze. 17ß-estradiol augmented the modulatory effects of escitalopram on the hippocampal levels of brain-derived neurotrophic factor and serotonin reuptake transporter as well as tumor necrosis factor-alpha without altering its effects on the gene expressions of serotonin receptor 1A, estrogen receptors alpha and beta, or acetylcholinestearase content. This combined therapy afforded synergistic protective effects on the brain histopathological architecture, particularly, the hippocampus. The antidepressant effect of 17ß-estradiol was abolished by pretreatment with estrogen receptor antagonist, tamoxifen (10mg/kg, p.o). In conclusion, 17ß-estradiol-induced antidepressant effect was confined to intracellular estrogen receptors activation. Moreover, 17ß-estradiol enhanced escitalopram's efficiency in ameliorating menopausal-like depression, via exerting synergistic neuroprotective and serotonin reuptake transporter modulatory effects, without impeding escitalopram-mediated cognitive improvement.