CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 24, Issue 10, 2025

ISG15 is a 15 kDa ubiquitin-like protein that covalently associates with its target proteins by a sequential enzymatic process known as ISGylation. Research on protein ISGylation has increased in recent years, and some studies have suggested that ISG15 is involved in neuroprotection and neurodegeneration mechanisms. This review outlines the current state of research on the implications of ISG15/ISGylation in other neuropathies such as malignant tumors, ataxia telangiectasia, ischemia, depression, and neurodegenerative diseases such as Alzheimer’s, Parkinson’s diseases, multiple sclerosis, and amyotrophic lateral sclerosis. Based on the studies reported to date, ISG15/ISGylation promotes the progression of brain tumors such as glioblastoma. Moreover, ISG15/ISGylation seems to play a dual role in neuropathies, demonstrating a neuroprotective effect when there is acute brain damage, but ISG15/ISGylation is associated with reduced neuroprotection when there is chronic damage, such as in neurodegenerative diseases.

Neurodegenerative diseases pose serious threats to public health worldwide. Biomarkers for neurodegenerative disorders are essential to enhance the diagnostic process in clinical settings and to aid in the creation and assessment of effective disease-modifying treatments. In recent times, affordable and readily available blood-based biomarkers identifying the same neurodegenerative disease pathologies have been created, potentially transforming the diagnostic approach for these disorders worldwide. Emerging relevant biomarkers for α-synuclein pathology in Parkinson's disease include blood-based indicators of overall neurodegeneration and glial activation. Cell-free DNA (cfDNA), an encouraging non-invasive biomarker commonly utilized in oncology and pregnancy, has demonstrated significant potential in clinical uses for diagnosing neurodegenerative disorders. In this section, we explore the latest cfDNA studies related to neurodegenerative disorders. Moreover, we present a perspective on the possible role of cfDNA as a diagnostic, therapeutic, and prognostic indicator for neurodegenerative disorders. This review provides a summary of the most recent progress in biomarkers for neurodegenerative disorders such as Alzheimer’s, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and traumatic brain injury.

Sitagliptin is a dipeptidyl peptidase-IV inhibitor approved for treating type 2 diabetes mellitus. It increases the active form of incretin Glucagon-like Peptide-1 (GLP-1). The GLP-1 peptide prevents damage to neurons due to its anti-inflammatory and anti-apoptotic activities. This article summarizes the studies assessing the neuroprotective properties of sitagliptin, especially through the GLP-1 pathway. The outcomes of experimental research indicate that sitagliptin has a decreasing effect on inflammation response. Sitagliptin decreases proinflammatory factors, such as Glial Fibrillary Acidic Protein (GFAP), Nuclear factor kappa B (NF-κB), Tumor Necrosis Factor-α (TNF-α), and Interleukin-6 (IL-6). It also decreases glutamate levels, the primary excitatory neurotransmitter. Furthermore, sitagliptin shows antioxidative and antiapoptotic effects. Lastly, sitagliptin may provide a novel agent for the management of neurological disease.

Brain ischemia-reperfusion injury (CIRI) refers to brain ischemia that leads to cellular dysfunction and cell death after a certain period, and ischemic damage is rescued by providing blood supply and reperfusion. And then, reperfusion includes components such as ion imbalance, mitochondrial dysfunction, oxidative stress, neuroinflammation, Ca²⁺ overload, and apoptosis, which do not cause tissue damage. Autophagy also occurs in CIRI due to oxygen deficiency, and autophagy has been shown to protect cells from ischemic injury. Flavonoids are a class of essential and diversified secondary plant metabolites found in different concentrations in leaves, flowers, roots, and fruits. Various studies have shown that flavonoids have healing qualifications such as anti-inflammatory, antimutagenic, anticarcinogenic, and antimicrobial. We aim to determine how flavonoids may affect signaling pathways and kinases in rats with CIRI. The results show that the activity of JAK2/STAT3, NF-κB, RhoA/ROCK, JNK-p38, and cAMKII signaling pathways increases under CIRI, and the PI3K/Akt/mTOR signaling pathway is suppressed. Studies using various flavonoids (kaempferol, chrysin, naringin, naringenin, quercetin, wogonin) have shown a neuroprotective effect by reversing the situation in signaling pathways during CIRI damage.