Gaber, H. A., E. M. Aly, E. S. Mohamed, M. Elfoly, M. A. Rabie, M. S. Talaat, and E. - S. M. El-Sayed, "Linking Cognitive Impairment with Amyloid-β Accumulation in Alzheimer's Disease: Insights from Behavioral Tests and FTIR Spectroscopy.", Journal of Alzheimer's disease reports, vol. 7, issue 1, pp. 1187-1200, 2023. Abstract18-ad_j_alzheimer_dis_reprt.pdf

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that progresses over time. Fourier Transform Infrared Spectroscopy (FTIR) analysis gives identification of the main metabolic changes that happen during neurodegeneration, by monitoring biochemical and molecular structure alterations that can help in AD diagnosis or treatment approach.

OBJECTIVE: The aim of the present work is to assess AD hallmarks in molecular structure of retina and monitor accumulation of amyloid beta(Aβ) in brain and retina during disease progression.

METHODS: AD induced in rats by Aluminum Chloride (AlCl). Retinal molecular structure during disease progression for 2,4,6 and 8 weeks was assessed by Fourier-transform infrared spectroscopy (FTIR) and the incidence of the disease was confirmed by a behavioural assessment; the Morris Water Maze test. Aβ levels in the brain and retina were also measured.

RESULTS: The results indicated that cognitive impairment starting from 6 weeks of AlCl administration. Retinal concentration of Aβ was significant increase ( < 0.05) from 2 weeks that precedes the observed increase of Aβ in the brain which appeared after 4 weeks of AlCl administration. Multivariate principal component analysis discovers that the variance noticed in the infrared spectra due to AD condition and it is time dependent for progression of the disease.

CONCLUSIONS: The accumulation of Aβ is a sensitive early biomarker in retina for AD. FTIR analysis of the retina revealed changes in hydrogen bond formation or destruction, alterations in lipid chain length and branching accompanied by depleted lipid content and carbonization, as well as degeneration of the retinal tissue due to AD.

Rabie, M. A., A. T. Ghoneim, M. I. Fahmy, M. F. El-Yamany, and R. H. Sayed, "Activation of alpha-7 nicotinic acetylcholine receptor by tropisetron mitigates 3-nitropropionic acid-induced Huntington's disease in rats: Role of PI3K/Akt and JAK2/NF-κB signaling pathways.", Chemico-biological interactions, vol. 393, pp. 110957, 2024. Abstract23-_tropisetron_cbi.pdf

Huntington's disease (HD) is an inheritable autosomal-dominant disorder that targets mainly the striatum. 3-Nitropropionic acid (3-NP) induces obvious deleterious behavioral, neurochemical, and histological effects similar to the symptoms of HD. Our study aimed to examine the neuroprotective activity of tropisetron, an alpha-7 neuronal nicotinic acetylcholine receptor (α-7nAChR) agonist, against neurotoxic events associated with 3-NP-induced HD in rats. Forty-eight rats were randomly allocated into four groups. Group I received normal saline, while Groups II, III and IV received 3-NP for 2 weeks. In addition, Group III and IV were treated with tropisetron 1 h after 3-NP administration. Meanwhile, Group IV received methyllycaconitine (MLA), an α-7nAChR antagonist, 30 min before tropisetron administration. Treatment with tropisetron improved motor deficits as confirmed by the behavioral tests and restored normal histopathological features of the striatum. Moreover, tropisetron showed an anti-oxidant activity via increasing the activities of SDH and HO-1 as well as Nrf2 expression along with reducing MDA level. Tropisetron also markedly upregulated the protein expression of p-PI3K and p-Akt which in turn hampered JAK2/NF-κB inflammatory cascade. In addition, tropisetron showed an anti-apoptotic activity through boosting the expression of Bcl-2 and reducing Bax expression and caspase-3 level. Interestingly, all the aforementioned effects of tropisetron were blocked by pre-administration of MLA, which confirms that such neuroprotective effects are mediated via activating of α-7nAChR. In conclusion, tropisetron showed a neuroprotective activity against 3-NP-induced HD via activating PI3K/Akt signaling and suppressing JAK2/NF-κB inflammatory axis. Thus, repositioning of tropisetron could represent a promising therapeutic strategy in management of HD.

Kamal, M. M., H. S. El-Abhar, D. M. Abdallah, K. A. Ahmed, and M. A. Rabie, "Mirabegron, dependent on β3-adrenergic receptor, alleviates mercuric chloride-induced kidney injury by reversing the impact on the inflammatory network, M1/M2 macrophages, and claudin-2.", International immunopharmacology, vol. 126, pp. 111289, 2024. Abstract19-mirabegron_int._immuno.pdf

The β3-adrenergic receptor (β3-AR) agonism mirabegron is used to treat overactive urinary bladder syndrome; however, its role against acute kidney injury (AKI) is not unveiled, hence, we aim to repurpose mirabegron in the treatment of mercuric chloride (HgCl)-induced AKI. Rats were allocated into normal, normal + mirabegron, HgCl untreated, HgCl + mirabegron, and HgCl + the β3-AR blocker SR59230A + mirabegron. The latter increased the mRNA of β3-AR and miR-127 besides downregulating NF-κB p65 protein expression and the contents of its downstream targets iNOS, IL-4, -13, and -17 but increased that of IL-10 to attest its anti-inflammatory capacity. Besides, mirabegron downregulated the protein expression of STAT-6, PI3K, and ERK the downstream targets of the above cytokines. Additionally, it enhanced the transcription factor PPAR-α but turned off the harmful hub HNF-4α/HNF-1α and the lipid peroxide marker MDA. Mirabegron also downregulated the CD-163 protein expression, which besides the inhibited correlated cytokines of M1 (NF-κB p65, iNOS, IL-17) and M2 (IL-4, IL-13, CD163, STAT6, ERK), inactivated the macrophage phenotypes. The crosstalk between these parameters was echoed in the maintenance of claudin-2, kidney function-related early (cystatin-C, KIM-1, NGAL), and late (creatinine, BUN) injury markers, besides recovering the microscopic structures. Nonetheless, the pre-administration of SR59230A has nullified the beneficial effects of mirabegron on the aforementioned parameters. Here we verified that mirabegron can berepurposedto treat HgCl-induced AKI by activating the β3-AR. Mirabegron signified its effect by inhibiting inflammation, oxidative stress, and the activated M1/M2 macrophages, events that preserved the proximal tubular tight junction claudin-2 via the intersection of several trajectories.

Kamal, R. M., M. M. Sabry, A. M. El-Halawany, M. A. Rabie, N. S. El Sayed, M. S. Hifnawy, and I. Y. Younis, "GC-MS analysis and the effect of topical application of essential oils of Pinus canariensis C.Sm., Cupressus lusitanica Mill. and Cupressus arizonica Greene aerial parts in Imiquimod-Induced Psoriasis in Mice.", Journal of ethnopharmacology, vol. 318, issue Pt B, pp. 116947, 2024. Abstract16-_psoriasis_ethanophaarmacology.pdf

ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, Coniferous plants, in particular Pinus and Cupressus species, have been used in the treatment of burns, skin infections, and immune-mediated inflammatory diseases such as psoriasis.

AIM OF THE STUDY: A comparative study between essential oils (EOs) extracted from aerial parts of three coniferous plants: Pinus canariensis C.Sm. (PC), Cupressus lusitanica Mill. (CL) and Cupressus arizonica Greene (CA), cultivated in Egypt, was designed to investigate their composition and their anti-psoriasis mechanism.

MATERIALS AND METHODS: The phytochemical profiles were confirmed using Gas Chromatography-Mass Spectrometry (GC-MS) method. In-vivo Imiquimod (IMQ)-induced psoriasis model was performed and EOs were applied topically and compared to mometasone cream as a standard subsequently histopathological analysis and inflammatory biomarkers were measured.

RESULTS: In GC-MS analysis, Monoterpene hydrocarbons, sesquiterpene hydrocarbons and oxygenated monoterpenes were the major detected classes in the three plants, except in Pinus canariensis essential oil, oxygenated monoterpenes were absent. A significant attenuation of imiquimod-induced psoriasis symptoms after topical application of P. canariensis C.Sm., and C. lusitanica Mill. essential oils were observed by reducing the psoriasis area severity index (PASI) score, alleviating histopathological alteration, restoring the spleen index, and decreasing serum levels of interleukins 23 and 17A. Indeed, the results of Pinus canariensis essential oil is comparable to mometasone and showed no significant difference from standard treatment. On the other hand, the topical application of C. arizonica essential oil failed to alleviate imiquimod-induced psoriasis symptoms as observed in the PSAI score, the histopathological investigation, and the spleen index.

CONCLUSION: The essential oils of P. canariensis C.Sm., and C. lusitanica Mill aerial parts could be promising candidates for psoriasis treatment and for further studies on inflammation-related skin diseases.

Mustafa, A. M., A. M. Shaheen, H. F. Zaki, and M. A. Rabie, "Nicorandil and carvedilol mitigates motor deficits in experimental autoimmune encephalomyelitis-induced multiple sclerosis: Role of TLR4/TRAF6/MAPK/NF-κB signalling cascade.", International immunopharmacology, vol. 127, pp. 111387, 2024. Abstract21-_nicorandil_int._immuno.pdf

Multiple sclerosis (MS) is an inflammatory demyelinating neurodegenerative disease that negatively affects neurotransmission. It can be pathologically mimicked by experimental autoimmune encephalomyelitis (EAE) animal model. ATP-sensitive potassium channels (K) plays a crucial role in the control of neuronal damage, however their role in MS are still obscure. Additionally, Carvedilol showed a promising neuroprotective activity against several neurological disorders. Therefore, the present study aimed to investigate the potential neuroprotective effect of K channel opener (nicorandil) as well as α and β adrenoceptor antagonist (Carvedilol) against EAE induced neurodegeneration in mice. Mice was treated with nicorandil (6 mg/kg/day; p.o.) and carvedilol (10 mg/kg/day; p.o.) for 14 days. Nicorandil and carvedilol showed improvement in clinical scoring, behaviour and motor coordination as established by histopathological investigation and immunohistochemical detection of MBP. Furthermore, both treatments downregulated the protein expression of TLR4/ MYD88/TRAF6 signalling cascade with downstream inhibition of (pT183/Y185)-JNK/p38 (pT180/Y182)-MAPK axis leading to reduction of neuroinflammatory status, as witnessed by reduction of NF-κB, TNF-α, IL-1β and IL-6 contents. Moreover, nicorandil and carvedilol attenuated oxidative damage by increasing Nrf2 content and SOD activity together with reduction of MDA content. In addition, an immunomodulating effect via inhibiting the gene expression of CD4, TGF-β, and IL-17 as well as TGF-β, IL-17, and IL-23 contents along with anti-apoptotic effect by decreasing Bax protein expression and Caspase-3 content and increasing Bcl-2 protein expression was observed with nicorandil and carvedilol treatments. In conclusion, nicorandil and carvedilol exerted a neuroprotective activity against EAE induced neuronal loss via inhibition of TLR4/MYD88/TRAF6/JNK/p38-MAPK axis besides antioxidant and anti-apoptotic effects.

Khedr, L. H., R. M. Rahmo, O. M. Eldemerdash, and M. A. Rabie, "Implication of M2 macrophage on NLRP3 inflammasome signaling in mediating the neuroprotective effect of Canagliflozin against methotrexate-induced cognitive impairment.", International immunopharmacology, vol. 130, pp. 111709, 2024. Abstract22-canagliflozin_int._immuno.pdf

Methotrexate (MTX), a chemotherapeutic antimetabolite, has been linked to cognitive impairment in cancer patients. MTX-induced metabolic pathway disruption may result in decreased antioxidant activity and increased oxidative stress, influencing hippocampal neurogenesis and microglial activation. Nuclear factor-kappa B (NF-κB), an oxidative stress byproduct, has been linked to MTX toxicity via the activation of NLRP3 inflammasome signaling. Macrophage activation and polarization plays an important role in tissue injury. This differentiation may be mediated via either the Toll-like receptor 4 (TLR4) or NLRP3 inflammasome. Interestingly, Canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor has been recently reported to exert anti-inflammatory effects by modulating macrophage polarization balance. This study aimed to investigate CANA's protective effect against MTX-induced cognitive impairment, highlighting the possible involvement of TLR4/ NF-κB crosstalk with NLRP3 inflammasome activation and macrophage polarization. Forty-eight Male Wistar rats were divided into 4 groups; (1) received saline orally for 30 days and intravenously on days 8 and 15. (2) received Canagliflozin (CANA; 20 mg/kg/day; p.o.) for 30 days. (3) received MTX (75 mg/kg, i.v.) on day 8 and 15, then they were injected with four i.p. injections of leucovorin (LCV): the first dose was 6 mg/ kg after 18 h, and the remaining doses were 3 mg/kg after 26, 42, and 50 h of MTX administration. (4) received MTX and LCV as in group 3 in addition to CANA as in group 2. MTX-treated rats showed cognitive deficits in spatial and learning memory as evidenced in the novel object recognition and Morris water maze tests. MTX exerted an oxidative effect which was evident by the increase in MDA and decline in SOD, GSH and GPx. Moreover, it exerted an inflammatory effect via elevated caspase-1, IL-1β and IL-8. CANA treatment restored cognitive ability, reduced MTX-induced oxidative stress and neuroinflammation via attenuation of TLR4/NF-κB/NLRP3 signaling, and rebalanced macrophage polarization by promoting the M2 phenotype. Hence, targeting molecular mechanisms manipulating macrophage polarization may offer novel neuroprotective strategies for preventing or treating MTX-induced immune modulation and its detrimental sequel.

Sadek, M. A., M. A. Rabie, N. S. El Sayed, H. M. Sayed, and E. S. R. A. A. A. KANDIL, "Neuroprotective effect of curcumin against experimental autoimmune encephalomyelitis-induced cognitive and physical impairments in mice: an insight into the role of the AMPK/SIRT1 pathway.", Inflammopharmacology, vol. 32, issue 2, pp. 1499-1518, 2024. Abstract20-_curcumin_inflammopharmacology.pdf

Multiple sclerosis (MS) is an incurable chronic neurodegenerative disease where autoimmunity, oxidative stress, and neuroinflammation collaboration predispose myelin sheath destruction. Interestingly, curcumin, a natural polyphenol, showed a neuroprotective effect in numerous neurodegenerative diseases, including MS. Nevertheless, the influence of curcumin against MS-induced cognitive impairment is still vague. Hence, we induced experimental autoimmune encephalomyelitis (EAE) in mice using spinal cord homogenate (SCH) and complete Freund's adjuvant, which eventually mimic MS. This study aimed not only to evaluate curcumin efficacy against EAE-induced cognitive and motor dysfunction, but also to explore a novel mechanism of action, by which curcumin exerts its beneficial effects in MS. Curcumin (200 mg/kg/day) efficacy was evaluated by behavioral tests, histopathological examination, and biochemical tests. Concisely, curcumin amended EAE-induced cognitive and motor impairments, as demonstrated by the behavioral tests and histopathological examination of the hippocampus. Interestingly, curcumin activated the adenosine monophosphate (AMP)-activated protein kinase/silent mating type information regulation 2 homolog 1 (AMPK/SIRT1) axis, which triggered cyclic AMP response element-binding protein/brain-derived neurotrophic factor/myelin basic protein (CREB/BDNF/MBP) pathway, hindering demyelination of the corpus callosum. Furthermore, AMPK/SIRT1 activation augmented nuclear factor erythroid 2-related factor 2 (Nrf2), a powerful antioxidant, amending EAE-induced oxidative stress. Additionally, curcumin abolished EAE-induced neuroinflammation by inhibiting Janus kinase 2 /signal transducers and activators of transcription 3 (JAK2/STAT3) axis, by various pathways, including AMPK/SIRT1 activation. JAK2/STAT3 inhibition halts inflammatory cytokines synthesis. In conclusion, curcumin's neuroprotective effect in EAE is controlled, at least in part, by AMPK/SIRT1 activation, which ultimately minimizes EAE-induced neuronal demyelination, oxidative stress, and neuroinflammation.

Khidr, H. Y., N. F. Hassan, S. S. Abdelrahman, M. R. El-Ansary, M. F. El-Yamany, and M. A. Rabie, "Formoterol attenuated mitochondrial dysfunction in rotenone-induced Parkinson's disease in a rat model: Role of PINK-1/PARKIN and PI3K/Akt/CREB/BDNF/TrKB axis.", International immunopharmacology, vol. 125, issue Pt B, pp. 111207, 2023. Abstract17-_formoterol_int._immuno.pdf

β2-adrenoreceptors (β2AR have been identified recently as regulators of the α-synuclein gene (SNCA), one of the key milieus endorsed in injury of dopamine neurons in Parkinson's disease (PD). Accumulation of α-synuclein leads to mitochondrial dysfunction via downregulation of mitophagy proteins (PINK-1 and PARKIN) and inhibition of mitochondria biogenesis (PGC-1α) along with an increase in the master inflammatory regulator NF-κB p65 production that provokes neurodegeneration and diminishes neuroprotective signaling pathway (PI3k/Akt/CREB/BDNF). Recently, formoterol exhibited a promising neuroprotective effect against neurodegenerative conditions associated with brain inflammation. Therefore, the present investigation aims to unveil the possible neuroprotective activity of formoterol, β2AR agonist, against rotenone-induced PD in rats. Rats received rotenone (1.5 mg/kg; s.c.) every other day for 3 weeks and cured with formoterol (25 μg/kg/day; i.p.) 1 hr. after rotenone administration, starting from day 11. Formoterol treatment succeeded in upregulating β2-adrenoreceptor expression in PD rats and preserving the function and integrity of dopaminergic neurons as witnessed by enhancement of muscular performance in tests, open field, grip strength-meter, and Rotarod, besides the increment in substantia nigra and striatal tyrosine hydroxylase immunoexpression. In parallel, formoterol boosted mitophagy by activation of PINK1 and PARKIN and preserved mitochondrial membrane potential. Additionally, formoterol stimulated the neuro-survival signaling axis via stimulation of PI3k/pS473-Akt/pS133-CREB/BDNF cascade to attenuate neuronal loss. Noteworthy formoterol reduces neuro-inflammatory status by decreasing NFκBp65 immunoexpression and TNF-α content. Finally, formoterol's potential as a stimulant therapy of mitophagy via the PINK1/PARKIN axis and regulation of mitochondrial biogenesis by increasing PGC-1α to maintain mitochondrial homeostasis along with stimulation of PI3k/Akt/CREB/BDNF axis.

Sayed, R. H., and M. A. Rabie, "Nandrolone Decanoate (Nan) Abusers and Concomitant Cannabis Use", Handbook of Substance Misuse and Addictions : Springer, 2022.
El-Latif, A. A. M., M. A. Rabie, R. H. Sayed, M. A. E. A. Fattah, and S. A. Kenawy, "Inosine attenuates rotenone-induced Parkinson's disease in rats by alleviating the imbalance between autophagy and apoptosis.", Drug development research, 2023. Abstract

Growing evidence points to impaired autophagy as one of the major factors implicated in the pathophysiology of Parkinson's disease (PD). Autophagy is a downstream target of adenosine monophosphate-activated protein kinase (AMPK). Inosine has already demonstrated a neuroprotective effect against neuronal loss in neurodegenerative diseases, mainly due its anti-inflammatory and antioxidant properties. We, herein, aimed at investigating the neuroprotective effects of inosine against rotenone-induced PD in rats and to focus on the activation of AMPK-mediated autophagy. Inosine successfully increased p-AMPK/AMPK ratio in PD rats and improved their motor performance and muscular co-ordination (assessed by rotarod, open field, and grip strength tests, as well as by manual gait analysis). Furthermore, inosine was able to mitigate the rotenone-induced histopathological alterations and to restore the tyrosine hydroxylase immunoreactivity in PD rats' substantia nigra. Inosine-induced AMPK activation resulted in an autophagy enhancement, as demonstrated by the increased striatal Unc-S1-like kinase1 and beclin-1 expression, and also by the increment light chain 3II to light chain 3I ratio, along with the decline in striatal mammalian target of rapamycin and p62 protein expressions. The inosine-induced stimulation of AMPK also attenuated neuronal apoptosis and promoted antioxidant activity. Unsurprisingly, these neuroprotective effects were antagonized by a preadministration of dorsomorphin (an AMPK inhibitor). In conclusion, inosine exerted neuroprotective effects against the rotenone-induced neuronal loss via an AMPK activation and through the restoration of the imbalance between autophagy and apoptosis. These findings support potential application of inosine in PD treatment.