Shafiek, M. S., R. Y. Mekky, N. N. Nassar, M. F. El-Yamany, and M. A. Rabie, "Vortioxetine ameliorates experimental autoimmune encephalomyelitis model of multiple sclerosis in mice via activation of PI3K/Akt/CREB/BDNF cascade and modulation of serotonergic pathway signaling.", European journal of pharmacology, vol. 982, pp. 176929, 2024 Nov 05. Abstract

Multiple sclerosis (MS) is a chronic condition characterized by immune cell infiltration and cytokine overproduction that led to myelin sheath inflammatory assaults, thus causing axonal destruction. The former consequently provokes motor impairment and psychological disorders. Markedly, depression is one of the most prevalent lifelong comorbidities that negatively impacts the quality of life in MS patients. Vortioxetine (VTX), a multi-modal molecule prescribed to manage depression and anxiety disorder, additionally, it displays a promising neuroprotective properties against neurodegenerative diseases such as Alzheimer's and Parkinson's. To this end, the present study investigated the potential therapeutic efficacy of VTX against experimental autoimmune encephalomyelitis (EAE) model of MS in mice. Notably, treatment with VTX significantly ameliorated EAE-induced motor disability, as evident by enhanced performance in open field, rotarod and grip strength tests, alongside a reduction in immobility time during the forced swimming test, indicating a mitigation of the depressive-like behavior; outcomes that were corroborated with histological examinations and biochemical analyses. Mechanistically, VTX enhanced serotonin levels by inhibiting both serotonin transporter (SERT) and indoleamine 2,3-dioxygenase (IDO) enzyme, thereby promoting the activation of serotonin 1A (5-HT) receptor. The latter triggered the stimulation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) cascade that entailed activation/phosphorylation of cAMP response element-binding protein (CREB). This activation increased brain derived neurotrophic factor (BDNF) and myelin basic protein (MBP) contents that mitigated demyelination in the corpus callosum. Furthermore, VTX suppressed phospho serine 536 nuclear factor kappa B (pS536 NF-κB p65) activity and reduced tumor necrosis factor-alpha (TNF-α) production. The results underscore VTX's beneficial effects on disease severity in EAE model of MS in mice by amending both inflammatory and neurodegenerative components of MS progression.

Shafiek, M. S., R. Y. Mekky, N. N. Nassar, M. F. El-Yamany, and M. A. Rabie, "Vortioxetine ameliorates experimental autoimmune encephalomyelitis model of multiple sclerosis in mice via activation of PI3K/Akt/CREB/BDNF cascade and modulation of serotonergic pathway signaling.", European journal of pharmacology, vol. 982, pp. 176929, 2024 Nov 05. Abstract

Multiple sclerosis (MS) is a chronic condition characterized by immune cell infiltration and cytokine overproduction that led to myelin sheath inflammatory assaults, thus causing axonal destruction. The former consequently provokes motor impairment and psychological disorders. Markedly, depression is one of the most prevalent lifelong comorbidities that negatively impacts the quality of life in MS patients. Vortioxetine (VTX), a multi-modal molecule prescribed to manage depression and anxiety disorder, additionally, it displays a promising neuroprotective properties against neurodegenerative diseases such as Alzheimer's and Parkinson's. To this end, the present study investigated the potential therapeutic efficacy of VTX against experimental autoimmune encephalomyelitis (EAE) model of MS in mice. Notably, treatment with VTX significantly ameliorated EAE-induced motor disability, as evident by enhanced performance in open field, rotarod and grip strength tests, alongside a reduction in immobility time during the forced swimming test, indicating a mitigation of the depressive-like behavior; outcomes that were corroborated with histological examinations and biochemical analyses. Mechanistically, VTX enhanced serotonin levels by inhibiting both serotonin transporter (SERT) and indoleamine 2,3-dioxygenase (IDO) enzyme, thereby promoting the activation of serotonin 1A (5-HT) receptor. The latter triggered the stimulation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) cascade that entailed activation/phosphorylation of cAMP response element-binding protein (CREB). This activation increased brain derived neurotrophic factor (BDNF) and myelin basic protein (MBP) contents that mitigated demyelination in the corpus callosum. Furthermore, VTX suppressed phospho serine 536 nuclear factor kappa B (pS536 NF-κB p65) activity and reduced tumor necrosis factor-alpha (TNF-α) production. The results underscore VTX's beneficial effects on disease severity in EAE model of MS in mice by amending both inflammatory and neurodegenerative components of MS progression.

El-Nawawy, T. M., Y. A. Adel, M. teaima, N. N. Nassar, A. A. Nemr, I. Al-Samadi, M. A. El-Nabarawi, and S. F. Elhabal, "Intranasal bilosomes in thermosensitive hydrogel: advancing desvenlafaxine succinate delivery for depression management.", Pharmaceutical development and technology, pp. 1-12, 2024. Abstract

Depression, the second biggest cause of disability worldwide, is widespread. Many antidepressant medications, including Desvenlafaxine Succinate (D.V.S.), function by elevating neurotransmitter levels at the synapse through the inhibition of reabsorption by neurons. However, the effectiveness of these treatments is often limited by their inability to reach the brain using conventional administration methods. Bilosome-stabilized nanovesicles containing bile salts have drawn much interest because of their adaptability and versatility in various applications. This study aimed to address this issue by formulating intranasal bilosomes incorporated into a mucoadhesive gel to deliver D.V.S. directly to the brain for depression treatment. The desvenlafaxine-loaded bilosomes were developed using a thin film hydration method based on the l-optimal design. They were intended to provide a more convenient route of administration for antidepressants, enhancing bioavailability and brain targeting through intranasal delivery. The study assessed the optimized bilosomes for particle size (311.21 ± 0.42 nm), Zeta potential (-)and encapsulation efficiency (99.53 ± 0.41%) and further evaluated them in and pharmacokinetics studies. Pharmacokinetic data reveal enhanced brain uptake compared to a free drug. A statistically optimized bilosome formulation was determined. The intranasal administration of mucoadhesive gel containing desvenlafaxine succinate-loaded bilosomes facilitated direct nose-to-brain drug delivery, improving brain bioavailability.

Kamel, A. S., S. M. Farrag, H. M. Mansour, N. N. Nassar, and M. A. Saad, "Dapagliflozin modulates neuronal injury via instigation of LKB1/p-AMPK/GABA R2 signaling pathway and suppression of the inflammatory cascade in an essential tremor rat model.", Expert opinion on therapeutic targets, vol. 27, issue 4-5, pp. 373-392, 2023. Abstract

BACKGROUND: However, disturbances in cellular energy demarcate neuronal hyperexcitability in essential tremor (ET); nevertheless, no available data relates energy sensors and GABAergic neurotransmission in ET. Noteworthy, reports have asserted dapagliflozin's (DAPA) role in enhancing autophagic sensors in other disorders. Herein, this study aims to investigate DAPA's impact on the GABA receptor subunit (GABA R2), notwithstanding the GABA A involvement, in an ET model.

METHODS: ET was induced by a single dose of harmaline (30 mg/kg; i.p.), while DAPA (1 mg/kg/day; p.o.) was given for 5 days before ET induction. The autophagic sensors were examined by injecting a single dose of dorsomorphin (DORSO) AMPK inhibitor (0.2 mg/kg; i.p.) on the 5 day before ET induction.

RESULTS: DAPA decreased the HAR-induced tremor score and alleviated motor disabilities observed in the open field, rotarod, wire grip strength, and gait kinematics confirmed by reduced electrical activity in electroencephalogram. In the cerebella, DAPA curbed HAR-evoked inflammatory cytokines, apoptotic markers, and glutamate while restoring the disturbed GABA, BDNF, LKB1, p-AMPK, and GABA R2 levels. DAPA's effect was mostly obliterated by DORSO.

CONCLUSION: DAPA offers a potential neuroprotective effect in ET by augmenting the neuronal inhibitory machinery via suppressing the inflammatory and excitotoxicity systems through LKB1/p-AMPK/GABA R2 signaling.

Rabie, M. A., H. I. Ibrahim, N. N. Nassar, and R. M. Atef, "Adenosine A receptor agonist, N6-cyclohexyladenosine, attenuates Huntington's disease via stimulation of TrKB/PI3K/Akt/CREB/BDNF pathway in 3-nitropropionic acid rat model.", Chemico-biological interactions, vol. 369, pp. 110288, 2023. Abstract

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive impairments. Intrastriatal injection of 3- nitropropionic acid (3NP) was used to induce HD-like symptoms by inhibiting succinate dehydrogenase enzyme (SDH) in the mitochondrial complex II. The adenosine A receptor has long been known to have a crucial role in neuroprotection, mainly by blocking Ca influx, which causes inhibition of glutamate (Glu) and a decline in its excitatory effects at the postsynaptic level. To this end, this study investigated the possible involvement of TrKB/PI3K/Akt/CREB/BDNF pathway in mediating protection afforded by the central N6-cyclohexyladenosine (CHA), an adenosine A receptor agonist. A single intrastriatal CHA injection (6.25 nM/1 μL); 45min after 3-NP injection, attenuated neuronal death, and improved cognitive and motor deficits caused by 3-NP neurotoxin. This effect was shown to parallel an enhanced activation of PI3K/Akt/CREB/BDNF axis as well as boosting pERK levels. Moreover, CHA attenuated neuroinflammatory and oxidative stress status via reducing NFκB p65, TNFα and iNOS contents and increasing SOD. Furthermore, immunohistochemical data showed a reduction in the glial fibrillary acidic protein (GFAP) immunoreactivity to a marker for astrocyte and microglia activation following CHA treatment. The results of this study suggest that CHA may have protective effect against HD via modulating oxidative stress, excitotoxic and inflammatory pathways.

Khedr, L. H., R. M. Eladawy, N. N. Nassar, and M. A. E. Saad, "Canagliflozin attenuates chronic unpredictable mild stress induced neuroinflammation via modulating AMPK/mTOR autophagic signaling.", Neuropharmacology, vol. 223, pp. 109293, 2023. Abstract

Although vast progress has been made to understand the pathogenesis of depression, existing antidepressant remedies, with several adverse effects, are not fully adequate. Interestingly, new emerging theories implicating an altered HPA-axis, tryptophan metabolism, neuroinflammation and altered gut integrity were proposed to further identify novel therapeutic targets. Along these lines, canagliflozin (CAN), a novel antidiabetic medication with anti-inflammatory and neuroprotective activity may present an effective treatment for depression; nevertheless, no studies have explored its effect on depressive disorder yet. To this end, this study aimed to investigate the possible antidepressant activity of CAN in CUMS and the mechanisms underlying its action on the gut-brain inflammation axis as well as the alteration in the TRY/KYN pathway in addition to its role in modulating the autophagic signaling cascade. Interestingly, CAN successfully attenuated the CUMS-induced elevations in despair and anhedonic behaviors as well as the elevated serum CORT. Furthermore, it enhanced gut integrity via hampering the CUMS-induced colonic inflammation and amending colonic tight junction proteins. The enhanced gut integrity was further corroborated by a notable anti-inflammatory and neuroprotective activity manifested via the observed mitigation of immune cell activation in addition to IDO hippocampal protein content and promotion of the autophagy cascade. Our findings postulate the possible anti-inflammatory and neuroprotective effects of CAN and the implication of TRY/KYN and AMPK/mTOR signaling pathways in the CUMS-induced MDD. Hence, this study shed light to the promising role of CAN in the augmentation of the current antidepressant treatments.

Zaki, O. S., N. N. Nassar, D. M. Abdallah, M. M. Safar, and R. A. Mohammed, "Cilostazol Alleviates NLRP3 Inflammasome-Induced Allodynia/Hyperalgesia in Murine Cerebral Cortex Following Transient Ischemia: Focus on TRPA1/Glutamate and Akt/Dopamine/BDNF/Nrf2 Trajectories.", Molecular neurobiology, vol. 59, issue 12, pp. 7194-7211, 2022. Abstract

Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. Cilostazol (CLZ) has pleiotropic effects including neuroprotection in several ravaging central disorders; nonetheless, its potential role in transient central ischemic-induced allodynia and hyperalgesia has not been asserted before. Rats were allocated into 4 groups; sham, sham + CLZ, and 45 min-bilateral carotid occlusion followed by a 48 h-reperfusion period either with or without CLZ (50 mg/kg; p.o) post-treatment. CLZ prolonged latency of hindlimb withdrawal following von Frey filaments, 4 °C cold, and noxious mechanical stimulations. Histopathological alterations and the immunoexpression of glial fibrillary acidic protein induced by I/R were reduced by CLZ in the anterior cingulate cortex (ACC) area, while, CLZ enhanced intact neuronal count. Meanwhile, CLZ modulated cerebral cortical glutamate, dopamine neurotransmission, and transient receptor potential ankyrin 1 (TRPA1). CLZ anti-inflammatory potential was mediated by the downregulated p65 NF-κB and sirtuin-1 enhancement to reduce nucleotide-binding domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), active caspase-1, and interleukin-1β, indicative of inflammasome deactivation. It also revealed an antioxidant capacity via boosting nuclear factor E2-related factor (Nrf2) enhancing glutathione through forkhead box protein O3a (FOXO3a) reduction. Additionally, CLZ triggered neuronal survival by promoting the p-content of Akt, TrkB, and CREB as well as BDNF content. A novel approach of CLZ in hindering global cerebral I/R-mediated neuropathy is firstly documented herein to forward its adjunct action via deactivating the NLRP3 inflammasome, besides enhancing Nrf2 axis, neuronal survival, and dopamine neurotransmission as well as inhibiting TRPA1 and excitotoxicity.

Tawfiq, R. A., N. N. Nassar, O. A. Hammam, R. M. Allam, M. M. Elmazar, D. M. Abdallah, and Y. M. Attia, "Obeticholic acid orchestrates the crosstalk between ileal autophagy and tight junctions in non-alcoholic steatohepatitis: Role of TLR4/TGF-β1 axis.", Chemico-biological interactions, vol. 361, pp. 109953, 2022. Abstract

An interplay exists between non-alcoholic steatohepatitis (NASH) and intestinal barrier dysfunction. A plethora of mechanisms are implicated in the regulation of intestinal integrity, among which is autophagy. Farnesoid X receptor (FXR) is a key metabolic regulator in the liver, however, its impact on ileal autophagy and barrier integrity in the context of NASH has not yet been unraveled. Accordingly, the present study aimed at investigating the impact of the FXR agonist, obeticholic acid (OCA), on modulating the aberrant ileal autophagy and barrier dysfunction in NASH, exploring the possible implication of the TLR4/TGF-β1 axis. High-fat diet (HFD) and dextran sulfate sodium (DSS, MW ∼40 kDa) were used for 13 weeks to induce NASH with distorted intestinal integrity in Swiss albino male mice. Post-treatment with OCA (5 mg/kg/day; p.o; 4 weeks), histopathological evaluation revealed a restoration of normal hepatic and ileal architectures. OCA partially restored intestinal permeability, as evidenced by the FITC-dextran leakage assay, with no change in serum LPS or LBP levels. Meanwhile, ileal expression of the tight junctions; claudin-1, zonulin-1, and occludin, was upregulated. Hepatic and ileal TLR-4 and TGF-β1 immunoreactivities were also decreased with no change observed in ileal phosphorylated Akt. In addition, ATG5 gene expression and LC3II/I protein ratio were upregulated in the ileum. Overall, the present study suggests a protective role of OCA on intestinal integrity in NASH, possibly through autophagy induction via interfering with the TLR4/TGF-β1 pathway.

El-Ghannam, M. S., M. A. Saad, N. N. Nassar, M. F. El-Yamany, and A. A. Z. El-Bahy, "Linagliptin ameliorates acetic acid-induced colitis via modulating AMPK/SIRT1/PGC-1α and JAK2/STAT3 signaling pathway in rats.", Toxicology and applied pharmacology, vol. 438, pp. 115906, 2022. Abstract

Ulcerative colitis is a chronic inflammatory disease, profoundly affecting the patient's quality of life and is associated with various complications. Linagliptin, a potent DPP- IV inhibitor, shows favorable anti-inflammatory effects in several animal model pathologies. To this end, the present study aimed to investigate the anti-inflammatory effect of linagliptin in a rat model of acetic acid-induced colitis. Moreover, the molecular mechanisms behind this effect were addressed. Accordingly, colitis was established by the administration of a 2 ml 6% acetic acid intrarectally and treatment with linagliptin (5 mg/kg) started 24 h after colitis induction and continued for 7 days. On one hand, the DPP-IV inhibitor alleviated the severity of colitis as evidenced by a decrease of disease activity index (DAI) scores, colon weight/length ratio, macroscopic damage, and histopathological deteriorations. Additionally, linagliptin diminished colon inflammation via attenuation of TNF-α, IL-6, and NF-κB p65 besides restoration of anti-inflammatory cytokine IL-10. On the other hand, linagliptin increased levels of p-AMPK, SIRT1, and PGC-1α while abolishing the increment in p-JAK2 and p-STAT3. In parallel linagliptin reduced mTOR levels and upregulated expression levels of SHP and MKP-1 which is postulated to mediate AMPK-driven JAK2/STAT3 inhibition. Based on these findings, linagliptin showed promising anti-inflammatory activity against acetic acid-induced colitis that is mainly attributed to the activation of the AMPK-SIRT1-PGC-1α pathway as well as suppression of the JAK2/STAT3 signaling pathway that might be partly mediated through AMPK activation.

Abdel Mageed, S. S., R. M. Ammar, N. N. Nassar, H. Moawad, and A. S. Kamel, "Role of PI3K/Akt axis in mitigating hippocampal ischemia-reperfusion injury via CB1 receptor stimulation by paracetamol and FAAH inhibitor in rat.", Neuropharmacology, vol. 207, pp. 108935, 2022. Abstract

AIMS: Acetaminophen or paracetamol (PAR), the recommended antipyretic in COVID-19 and clinically used to alleviate stroke-associated hyperthermia interestingly activates cannabinoid receptor (CB1) through its AM404 metabolite, however, to date, no study reports the in vivo activation of PAR/AM404/CB1 axis in stroke. The current study deciphers the neuroprotective effect off PAR in cerebral ischemia/reperfusion (IR) rat model and unmasks its link with AM404/CB1/PI3K/Akt axis.

MATERIALS AND METHODS: Animals were allocated into 5 groups: (I) sham-operated (SO), (II) IR, (III) IR + PAR (100 mg/kg), (IV) IR + PAR (100 mg/kg) + URB597; anandamide degradation inhibitor (0.3 mg/kg) and (V) IR + PAR (100 mg/kg) + AM4113; CB1 Blocker (5 mg/kg). All drugs were intraperitoneally administered at the inception of the reperfusion period.

KEY FINDINGS: PAR administration alleviated the cognitive impairment in the Morris Water Maze as well as hippocampal histopathological and immunohistochemical examination of GFAP. The PAR signaling was associated with elevation of anandamide level, CB1 receptor expression and survival proteins as p-Akt. P-ERK1/2 and p-GSK3β. Simultaneously, PAR increased hippocampal BDNF and β-arrestin1 levels and decreased glutamate level. PAR restores the deranged redox milieu induced by IR Injury, by reducing lipid peroxides, myeloperoxidase activity and NF-κB and increasing NPSH, total antioxidant capacity, nitric oxide and Nrf2 levels. The pre-administration of AM4113 reversed PAR effects, while URB597 potentiated them.

SIGNIFICANCE: PAR poses a significant neuroprotective effect which may be mediated, at least in part, via activation of anandamide/CB1/PI3K/Akt pathway in the IR rat model.