Methylprednisolone (MPS) has demonstrated considerable merits in the clinical treatment of spinal cord injury (SCI), yet its application is conspicuously constrained by the narrow therapeutic time window and grave side effects, such as gastrointestinal bleeding. Furthermore, the impediment posed by the blood-spinal cord barrier (BSCB) hinders the effective delivery of drugs to the injured tissue. In this study, we developed a nanodrug that exhibited programmed responsiveness to matrix metalloproteinases (MMPs) and reactive oxygen species (ROS). The surface peptide of the neutrally charged nanodrug was precisely tailored to be cleaved by MMPs at the SCI site, converting it to a robustly cationic entity, which facilitated efficient penetration of the BSCB. Subsequently, the encapsulated drugs underwent a swift release process within the SCI microenvironment, characterized by heightened ROS expression. The results showed that an impressive 7.42% of intravenously administered nanodrugs were successfully targeted to the lesion site, which inhibited cell apoptosis and fostered the survival of damaged neurons while concurrently mitigating the side effects compared to unmodified drugs. Besides, our investigation uncovered that MPS possessed the capability to modulate the polarization of macrophages, regulating the production of proinflammatory and anti-inflammatory cytokines, ultimately culminating in the restoration of motor function in injured mice. In essence, this ingeniously crafted nanodrug offers invaluable insights and guidance for the clinical management of SCI.

Mechanistic Insights into the Antidepressant Effects of the Angelica sinensis and Ligusticum chuanxiong Herb Pair: Involvement of the PI3K/AKT Signaling Pathway.

Prion diseases are fatal neurodegenerative disorders characterized by profound neuronal damage. Despite evidence supporting a neuroprotective role for β-synuclein (β-syn) in neurodegeneration, its potential functions and mechanisms in prion disease have not been elucidated. To investigate the role of β-syn, we systematically analyzed its alterations in the central nervous system of several prion-infected rodent models and cell models. A series of biochemical, cellular, and immunofluorescence assays were conducted to explore the relationship between β-syn and protein kinase B (Akt) signaling and between β-syn and prion protein (PrP), and its neuroprotective role in prion disease. Student’s t-test was used for statistics. At the terminal stage of prion disease, β-syn and Akt exhibited a parallel and remarkable decrease in rodent brains, contrasting with the slight but significant increase observed at early to middle stages. Dual-stained immunofluorescence assays confirmed that β-syn is localized within NeuN-positive neurons. Further structural and functional analyses revealed a high-affinity molecular interaction between β-syn and Akt, with the N-terminal region of β-syn being essential for binding to Akt1. In a cell model of PrP aggregation, β-syn overexpression suppressed cytochrome c-induced apoptosis, which was demonstrated by decreased levels of cleaved caspase-3. Notably, this anti-apoptotic effect was partially abolished upon Akt knockdown, indicating a dependence on Akt signaling. Moreover, colocalization of β-syn and PrP was observed in rodent brains. Consistently, in cellular models of prion infection and PrP aggregation, β-syn overexpression not only reduced PrP levels but also ameliorated its aberrant histological distribution. Our findings demonstrate that the anti-apoptotic activity of β-syn, mediated via Akt signaling, is severely lost during prion infection, thereby suggesting a mechanism of intrinsic neuronal vulnerability and revealing a novel therapeutic strategy.

(1) Background: Bioactive peptides from marine and plant sources show neuroprotective potential, yet how their combination ratios affect memory regulation via the gut–brain axis remains unclear. This study investigated the effects of different ratios of marine peptide QMDDQ (Glutamine-Methionine-Aspartate-Aspartate-Glutamine) and plant peptide AGLPM (Alanine-Glycine-Leucine-Proline-Methionine) on scopolamine-induced memory impairment in mice. (2) Methods: Cognitive function was assessed using the Morris water maze and novel object recognition tests. Nissl staining, microplate-based assays for acetylcholine (ACh) content and acetylcholinesterase (AChE) activity, Western blotting for neurotrophic factors, LC-MS/MS-based intestinal peptide profiling, and HPLC-based brain amino acid analysis were performed. (3) Results: The 1:1 ratio most effectively restored learning and memory, regulated hippocampal cholinergic function, mitigated neuronal damage, and elevated BDNF, NGF, and NTF-3 expression. In the gut, peptides were hydrolyzed into glutamate- and proline-rich fragments, which influenced brain amino acid balance by elevating glutamate and proline levels while reducing NH3-related signaling. (4) Conclusions: These results highlight the ratio-dependent efficacy of QMDDQ-AGLPM combinations and provide evidence for a gut peptide remodeling-brain metabolic link relevant to cognitive impairment.

TET3 SUMOylation enhances neuronal DNA damage repair and neuroprotection after ischemic stroke.

Protective effects of phosphodiesterase 5 inhibitor, mirodenafil, on traumatic brain injury-induced neuronal death.

Neuroprotection via IGF-1 Neuronal Signaling Activation by Melatonin and Edaravone Synergy in Methylmercury-Induced ALS-like Neurotoxicity: Comprehensive Analysis of Brain Regions, Spinal Cord, CSF, and Blood Plasma.

ALKBH5-mediated autophagic flux impairment is involved in bilirubin neurotoxicity.

Sphingosine-1-phosphate attenuates seizures and cognitive deficits, associated with reduced hippocampal IL-1β in a PTZ-induced epilepsy model.

Septin 2: A direct target of Ginsenoside Rg1 mediating its neuroprotective effects.

Exogenous hydrogen sulphide alleviates diabetes-associated cognitive decline by inhibiting ferroptosis through Nrf2/GPX4 signalling pathway.

Methamphetamine regulates microglial polarization and glycolytic activity to promote Parkinson's disease through the LIPH/LPA/PI3K/AKT signaling axis.

Maternal vitamin D deficiency during pregnancy impaired offspring's spatial learning and memory ability: Insights into the role of the CaMKK2/AMPK/FoxO3a pathway.

Banxia Houpo Decoction reduces lysosomal leakage of prefrontal astrocytes through the OGT-CTSB-NLRP3 pathway to improve depressive-like behaviors.

Exogenous mitochondrial transfer alleviates neurodegeneration in Parkinson's disease model by improving mitochondrial function.

Neuroprotective effects of Yizhi decoction via inhibition of PINK1/Parkin-mediated mitophagy in the prefrontal cortex of rats with attention deficit hyperactivity disorder.

Epigenetic reprogramming for ocular aging and disease: Mechanisms, biomarkers, and the road to the clinic.

Ophiopogon polysaccharide can improve memory impairment induced by sleep deprivation in aged rats by regulating gut microbiota and inhibiting TLR4/NF-κB pathway in hippocampus.

Differential neuroinflammatory trajectories in the hippocampus and prefrontal cortex after acute LPS administration.

Intergenerational neurotoxicity mediated by maternal plasma metabolite profile remodeling following maternal atrazine exposure.