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.

Cilostazol novel neuroprotective mechanism against rotenone-induced Parkinson's disease in rats: Correlation between Nrf2 and HMGB1/TLR4/PI3K/Akt/mTOR signaling.

Neuroinflammation induced by activation of the high mobility group box 1/ toll-like receptor 4 (HMGB1/TLR4) axis is one of the principal mechanisms involved in dopaminergic neuronal loss in Parkinson's disease (PD), and its activation exacerbates oxidative stress augmenting neurodegeneration. AIMS: This study investigated the novel neuroprotective effect of cilostazol on rotenone-intoxicated rats focusing on the HMGB1/TLR4 axis, erythroid-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1), and phosphoinositide 3-kinase (PI3K)/Protein kinase B (Akt)/the mammalian target of rapamycin (mTOR) pathway. The aim is extended to correlate the Nrf2 expression with all assessed parameters as promising therapeutic targets for neuroprotection. MAIN METHODS: Our experiment was designed as follows: vehicle group, cilostazol group, rotenone group (1.5 mg/kg, s.c), and the rotenone pretreated with cilostazol (50 mg/kg, p.o.) group. Eleven rotenone injections were injected day after day, while cilostazol was administered daily for 21 days. KEY FINDINGS: Cilostazol significantly improved the neurobehavioral analysis, the histopathological examination, and dopamine levels. Moreover, the immunoreactivity of tyrosine hydroxylase (TH) in substantia nigra pars compacta (SNpc) enhanced. These effects were associated with enhancement of the antioxidant expression of Nrf2 and HO-1 by 1.01 and 1.08-fold, respectively, and repression of HMGB1/TLR4 pathway by 50.2 % and 39.3 %, respectively. Upregulation of the neuro-survival PI3K and Akt expression by 2.26 and 2.69-fold, respectively, and readjusting mTOR overexpression. SIGNIFICANCE: Cilostazol exerts a novel neuroprotective strategy against rotenone-induced neurodegeneration via activation of Nrf2/HO-1, suppression of HMGB1/TLR4 axis, upregulation of PI3K/Akt besides mTOR inhibition that compels more investigations with different PD models to clarify its precise role.

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.

Umuhengerin Neuroprotective Effects in Streptozotocin-Induced Alzheimer's Disease Mouse Model via Targeting Nrf2 and NF-Kß Signaling Cascades.

Alzheimer's disease (AD) is the most common type of dementia and is characterized by advanced cognitive deterioration, deposition of Aß (amyloid-beta), and the formation of neurofibrillary tangles. Administration of streptozotocin (STZ) via the intracerebroventricular (ICV) route is a reliable model resembling sporadic AD (SAD) associated neuropathological changes. The present study was undertaken to explore the neuroprotective effects of the methoxy flavonoid, umuhengerin, in an STZ-induced SAD mouse model as a potential therapy for AD. Mice were injected once with STZ (3 mg/kg, ICV), followed by daily administration of umuhengerin (orally, 30 mg/kg) or the positive control donepezil (orally, 2.5 mg/kg) for 21 days. The pharmacological activity of umuhengerin was assessed through estimation of oxidative stress and inflammatory markers via mouse ELISA kits, Western blot analysis, and brain histopathological examination. Morris water maze test was also conducted to investigate umuhengerin-induced cognitive enhancement. The results showed that umuhengerin attenuated STZ-produced neuroinflammation and oxidative stress with a notable rise in the expression of Nrf2 (nuclear factor erythroid 2-related factor 2). In contrast, it downregulated Keap-1 (Kelch-like ECH associated protein 1), as well as elevated brain contents of GSH (reduced glutathione) and HO-1 (heme oxygenase-1). STZ-injected animals receiving umuhengerin showed marked downregulation of the nuclear factor kappa beta (NF-Kßp65) and noticeable increment in the expression of its inhibitor kappa beta alpha protein (IKßα), as well as prominent reduction in malondialdehyde (MDA), H2O2 (hydrogen peroxide), and TNF-α (tumor-necrosis factor-alpha) contents. Β-secretase protein expression and acetylcholinesterase (AchE) activity were also diminished upon umuhengerin injection in the STZ group, leading to decreased Aß formation and cognitive improvement, respectively. In conclusion, umuhengerin neuroprotective effects were comparable to the standard drug donepezil; thus, it could be an alternative approach for AD management.

Mangostanaxanthone IV Ameliorates Streptozotocin-Induced Neuro-Inflammation, Amyloid Deposition, and Tau Hyperphosphorylation via Modulating PI3K/Akt/GSK-3ß Pathway.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by amyloid deposition and neurofibrillary tangles formation owing to tau protein hyperphosphorylation. Intra-cerebroventricular (ICV) administration of streptozotocin (STZ) has been widely used as a model of sporadic AD as it mimics many neuro-pathological changes witnessed in this form of AD. In the present study, mangostanaxanthone IV (MX-IV)-induced neuro-protective effects in the ICV-STZ mouse model were investigated. STZ (3 mg/kg, ICV) was injected once, followed by either MX-IV (30 mg/kg/day, oral) or donepezil (2.5 mg/kg/day, oral) for 21 days. Treatment with MX-IV diminished ICV-STZ-induced oxidative stress, neuro-inflammation, and apoptosis which was reflected by a significant reduction in malondialdehyde (MDA), hydrogen peroxide (H2O2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) brain contents contrary to increased glutathione (GSH) content. Moreover, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase content and cleaved caspase-3 activity were reduced together with a marked decrement in amyloid plaques number and phosphorylated tau expression via PI3K/Akt/GSK-3ß pathway modulation, leading to obvious enhancement in neuronal survival and cognition. Therefore, MX-IV is deemed as a prosperous nominee for AD management with obvious neuro-protective effects that were comparable to the standard drug donepezil.

Targeting central ß2 receptors ameliorates streptozotocin-induced neuroinflammation via inhibition of glycogen synthase kinase3 pathway in mice.

Alzheimer's disease (AD) is portrayed by progressive cognitive decline and pathological deposition of amyloid plaques as well as neurofibrillary tangles. Most of AD cases are sporadic, resulting from overlap of various environmental and genetic factors. Intra-cerebroventricular injection of streptozotocin (STZ) leads to insulin resistance brain state accompanied by memory decline, oxidative stress, and neuro-degeneration which mimic the pathologies associated with sporadic Alzheimer's disease (SAD). In the current study, protective effects of formoterol in STZ-induced SAD were studied. Formoterol-induced improvement in cognition was confirmed using Morris water maze and Y maze together with histopathological evidences. Moreover, prominent declines in oxidative stress, neuro-inflammation, and apoptotic parameters were recorded upon its injection in STZ-induced SAD mouse model. This was manifested by the decrement of malondialdehyde, hydrogen peroxide, interleukin-1ß, interleukin-6, tumor necrosis factor-α, and caspase-3levels contrary to reduced glutathione and interleukin-10 increments. Formoterol also reversed STZ-induced alteration in acetylcholine and glutamate levels. Furthermore, it could be concluded that formoterol was capable of combating STZ-induced neuro-inflammation and retarding the development of the main pathological hallmarks of AD through glycogen synthase kinase-3 deactivation.