Neuroinflammation, a pervasive hallmark in many neurological and neuropsychiatric diseases, is largely dictated by the functional phenotypic dynamics of microglia, the immune system of the brain. Recent data illustrate that these phenotypic changes, from neuroprotective scavenging to neurotoxic pro-inflammatory effects, are intrinsically regulated by microglial metabolic repolarization. This review synthesizes understanding of discrete microglial metabolic phenotypes like the glycolytic reliance of pro-inflammatory (M1-like) microglia and the oxidative phosphorylation/fatty acid oxidation bias of anti-inflammatory/resolving (M2-like) microglia. We discuss how central metabolic sensors like AMPK, mTOR, and HIF-1α oversee these metabolic shifts in response to disease-targeted pathologies in Alzheimer’s, Parkinson’s, Multiple Sclerosis, ischemic stroke, and traumatic brain injury. Moreover, we review innovative therapeutic strategies directed toward microglial metabolism, involving pharmacological modulators (e.g., metformin, rapamycin, and ketone bodies), nutritional interventions (e.g., ketogenic diets), and modulation of gut microbiota. By tightly specific re-tuning of microglial cells’ bioenergetics, these approaches enable unprecedented opportunities to counteract neuroinflammation, enhance pathological clearance, and induce neuroprotection, paving the way for a new generation of disease-modifying therapies of neurodegenerative disorders.

Parkinson's disease (PD) is the second most common neurodegenerative disease that represents the commonest movement disorder in the elderly population. PD neuropathology is due to the progressive deposition of mutant alpha synuclein (α-Syn) in the dopaminergic neurons (DNs) of the substantia nigra pars compacta (SNpc). Additionally, amyloid protein (Aβ) and tau protein, which are the hallmarks of Alzheimer's disease (AD), are also involved in PD and the development of PD-related dementia. Notably, α-Syn, Aβ, tau protein, and neuronal cholesterol metabolism are regulated by a transmembrane protein, low-density lipoprotein receptor-related protein 1 (LRP1), which is highly expressed in the SNpc and mediates the transmission and seeding of α-Syn in the brain. It has been reported that deletion of the LRP1 gene protects against the development and progression of PD. However, LRP1 has a neuroprotective effect against AD neuropathology by improving Aβ clearance across the blood-brain barrier (BBB) and enhancing tau protein proteolysis. Nevertheless, the exact role of LRP1 in PD neuropathology, mostly about α-Syn, is not completely explained. Therefore, this review aims to discuss and explain the role of LRP1 in PD and how targeting neuronal LRP1 may be helpful in the management of PD. In this review, online databases were involved by searching Scopus, Web of Science, and other search engine to detect the relationship between the expression of LRP1 and the pathogenesis of PD.

Parkinson's disease (PD) is the most common movement disorder, affecting approximately 1% of the general population over 65 years of age. PD is commonly associated with the development of motor and non-motor symptoms. Non-motor symptoms arise decades earlier than motor symptoms due to the degeneration of GABAergic, serotonergic, and other neurons involved in autonomic regulation. However, motor symptoms in PD are developed due to degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc) of midbrain. The PD neuropathology is related to the progressive loss of the dopaminergic neurons in the SNpc of midbrain. Particularly, dysfunction of serotonergic system is implicated in the development of non-motor symptoms such as sleep disorders, cognitive dysfunction, depression and anxiety. In addition, dysfunction of serotonergic neurons which affects the dopaminergic neurons in the SNpc leads to the development of motor symptoms. Moreover, dysfunction of serotonergic neurons is associated with the development of L-dopamine (L-DOPA)-induced dyskinesia. Consistently, administration of serotonin (5-HT) receptor agonist attenuates the development of L-DOPA-induced dyskinesia. These findings emphasized the possible role of serotonergic system in PD. However, the underlying mechanisms that mediate the latent effect of 5-HT in PD are not completely elucidated. Therefore, this mini-review aims to discuss the exact role of 5-HT in PD, and how the 5-HT modulators affect PD neuropathology.

The bidirectional relationship between epilepsy and depression illustrates shared neurobiological mechanisms of neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and glutamatergic dysfunction. Depression is present in 20–55% of people with epilepsy, far greater than in the general population, while depression doubles epilepsy risk 2.5-fold, indicating shared pathophysiology. Neuroinflammatory mediators (interleukin-6, tumor necrosis factor alpha, high-mobility group box 1) establish a vicious cycle: seizures exacerbate inflammation and mood disruption, and stress lowers seizure thresholds. Hippocampal damage and cortisol toxicity also link these disorders, with early life stress imprinting lifelong risk via epigenetic alteration. Genetic studies identify pleiotropic genes (brain-derived neurotrophic factor) that regulate synaptic plasticity, serotonin activity, and immune responses. New treatments target shared pathways: ketamine and AMPAkines normalize glutamate tone; mGluR5 antagonists attenuate hyperexcitability and inflammation; DNA methyltransferase inhibitors reverse aberrant DNA methylation; and probiotics manipulate the gut–brain axis by boosting neuroprotective metabolites like butyrate. Despite challenges—transient effects, precision dosing, and blood–brain barrier penetration—these advances constitute a paradigm shift toward mechanistic repair rather than symptom management. The way forward includes clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing, biomarker-led therapies, and combination approaches (e.g., ketamine and probiotics). Such comorbidity needs to be managed holistically through integrated neuropsychiatry care, offering hope to patients with treatment-refractory symptoms.