Balapal S. Basavarajappa

The endocannabinoid system (eCBS) is a versatile neuromodulatory network that orchestrates synaptic plasticity, reward processing, and neuronal homeostasis. Increasing evidence implicates eCBS dysregulation in both addiction and neurodegenerative (ND) disorders, suggesting overlapping molecular and cellular mechanisms underlying these conditions. This review synthesizes recent advances in understanding how eCBS components—cannabinoid receptors (CB1 and CB2), endogenous ligands (anandamide and 2-arachidonoylglycerol), and their metabolic enzymes—modulate dopaminergic and glutamatergic signaling within reward and reinforcement circuits. Chronic exposure to drugs of abuse, including alcohol, opioids, cocaine, and methamphetamine, perturbs eCBS homeostasis, promoting oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and protein aggregation—pathological features common to Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. These overlapping mechanisms disrupt neuronal integrity and contribute to progressive neurotoxicity, highlighting shared pathogenic pathways between addiction and neurodegeneration. Despite these advances, critical gaps remain in delineating how substance-induced eCBS alterations precipitate neurodegenerative cascades. Addressing these gaps will be essential for harnessing the eCBS as a therapeutic target to mitigate addiction-driven neurotoxicity and age-related cognitive decline.

The endocannabinoid system (eCBS) is a versatile neuromodulatory network that orchestrates synaptic plasticity, reward processing, and neuronal homeostasis. Increasing evidence implicates eCBS dysregulation in both addiction and neurodegenerative (ND) disorders, suggesting overlapping molecular and cellular mechanisms that underlie these conditions. This review synthesizes current advances in understanding how eCBS components—cannabinoid receptors (CB1 and CB2), endogenous ligands (anandamide and 2-arachidonoylglycerol), and their metabolic enzymes—modulate dopaminergic and glutamatergic signaling within reward and reinforcement circuits. Chronic exposure to drugs of abuse, including alcohol, cocaine, and methamphetamine, perturbs eCBS homeostasis, promoting oxidative stress, neuroinflammation, excitotoxicity, and protein aggregation—pathological features common to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Experimental studies demonstrate that pharmacological or genetic manipulation of eCBS components can mitigate neurotoxic outcomes, emphasizing their homeostatic and neuroprotective potential. Despite these advances, mechanistic gaps remain regarding how substance-induced eCBS alterations precipitate neurodegenerative cascades. Addressing these gaps will be critical for leveraging the eCBS as a therapeutic target to counteract addiction-driven neurotoxicity and age-related cognitive decline.

Cannabis sativa is known for producing over 120 distinct phytocannabinoids, with Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) being the most prominent, primarily in their acidic forms. Beyond Δ⁹-THC and CBD, a wide array of lesser-known phytocannabinoids, along with terpenes, flavonoids, and alkaloids, demonstrate diverse pharmacological activities, interacting with the endocannabinoid system (eCB) and other biological pathways. These compounds, characterized by phenolic structures and hydroxyl groups, possess lipophilic properties, allowing them to cross the blood–brain barrier (BBB) effectively. Notably, their antioxidant, anti-inflammatory, and neuro-modulatory effects position them as promising agents in treating neurodegenerative disorders. While research has extensively examined the neuropsychiatric and neuroprotective effects of Δ⁹-THC, other minor phytocannabinoids remain underexplored. Due to the well-established neuroprotective potential of CBD, there is growing interest in the therapeutic benefits of non-psychotropic minor phytocannabinoids (NMPs) in brain disorders. This review highlights the emerging research on these lesser-known compounds and their neuroprotective potential. It offers insights into their therapeutic applications across various major neurological conditions.

Cannabis sativa is known for producing over 120 distinct phytocannabinoids, with Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) being the most prominent, primarily in their acidic forms. Beyond Δ9-THC and CBD, a wide array of lesser-known phytocannabinoids, along with terpenes, flavonoids, and alkaloids, demonstrate diverse pharmacological activities, interacting with the endocannabinoid system (eCB) and other biological pathways. These com-pounds, characterized by phenolic structures and hydroxyl groups, possess lipophilic properties, allowing them to cross the blood-brain barrier (BBB) effectively. Notably, their antioxidant, an-ti-inflammatory, and neuro-modulatory effects position them as promising agents in treating neu-rodegenerative disorders. While research has extensively examined the neuropsychiatric and neuroprotective effects of Δ9-THC, other minor phytocannabinoids remain underexplored. Given the well-established neuroprotective potential of CBD, there is growing interest in the therapeutic benefits of non-psychotropic minor phytocannabinoids (NMPs) in brain disorders. This review highlights the emerging research on these lesser-known compounds and their neuroprotective potential. It offers insights into their therapeutic applications across various major neurological conditions.

Endosomal system dysfunction within neurons is a prominent early feature of Alzheimer’s disease (AD) pathology. Multiple AD risk factors are regulators of endocytosis and are known to cause hyper-activity of the early-endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption and cholinergic neurodegeneration. Adaptor protein containing Pleckstrin homology domain, Phosphotyrosine binding domain, Leucine zipper motif (APPL1), an important rab5 effector protein and signaling molecule, has been shown in vitro to interface between endosomal and neuronal dysfunction through a rab5-activating interaction with the BACE1-generated C-terminal fragment of amyloid precursor protein (APP-βCTF), a pathogenic APP fragment generated within endosomal compartments. To understand the contribution of APPL1 to AD-related endosomal dysfunction in vivo , we generated a transgenic mouse model over-expressing human APPL1 within neurons (Thy1-APPL1 mice). Strongly supporting the important endosomal regulatory roles of APPL1 and their relevance to AD etiology, Thy1-APPL1 mice develop enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We demonstrated pathophysiological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), degeneration of large projection cholinergic neurons of the basal forebrain, and impaired hippocampal-dependent memory. Our evidence shows that neuronal APPL1 elevation modeling its functional increase in the AD brain induces a cascade of AD-related pathological effects within neurons, including early endosome anomalies, synaptic dysfunction, and selective neurodegeneration. Our in vivo model highlights the contributions of APPL1 to the pathobiology and neuronal consequences of early endosomal pathway disruption and its potential value as a therapeutic target. Significance Statement: Neuronal endosome dysfunction appears early in Alzheimer’s disease (AD) and is linked to memory loss. Genes and risk factors associated with AD often increase rab5 activity, a protein that disrupts endosomal signalling when hyperactivated. APPL1, a key rab5 partner, worsens this dysfunction via its interaction with APP-βCTF, a protein fragment associated with AD. To explore APPL1’s role, we created a genetically modified mouse that overexpresses APPL1 in neurons. This model provides the first in vivo evidence that APPL1 overexpression triggers key AD-like effects: rab5 hyperactivation, enlarged early endosomes, loss of cholinergic neurons, reduced synaptic plasticity in memory-related brain regions, and memory deficits. These findings highlight APPL1’s role in AD pathogenesis and its potential as a therapeutic target.

Recent genomics and epigenetic advances have empowered the exploration of DNA/RNA methylation and histone modifications crucial for gene expression in response to stress, aging and disease. Interes... Plain language summary Scientists have made progress in understanding how our genes and their chemical modifications play a role in how our brains respond to stress, age and diseases. They are part... Tweetable abstract Unraveling the brain's epigenetic dance: histone acetylation changes play a key role in Alzheimer's, Parkinson's and Huntington's. Explores potential therapeutic avenues and insi...

The brain’s ability to strengthen or weaken synaptic connections is often termed synaptic plasticity. It has been shown to function in brain remodeling following different types of brain damage (e.g., drugs of abuse, alcohol use disorders, neurodegenerative diseases, and inflammatory conditions). Although synaptic plasticity mechanisms have been extensively studied, how neural plasticity can influence neurobehavioral abnormalities in alcohol use disorders (AUDs) is far from being completely understood. Alcohol use during pregnancy and its harmful effects on the developing offspring are major public health, social, and economic challenges. The significant attribute of prenatal alcohol exposure on offspring is damage to the central nervous system (CNS), causing a range of synaptic structural, functional, and behavioral impairments, collectively called fetal alcohol spectrum disorder (FASD). Although the synaptic mechanisms in FASD are limited, emerging evidence suggests that FASD pathogenesis involves altering a set of molecules involved in neurotransmission, myelination, and neuroinflammation. These studies identify several immediate and long-lasting changes using many molecular approaches that are essential for synaptic plasticity and cognitive function. Therefore, they can offer potential synaptic targets for the many neurobehavioral abnormalities observed in FASD. In this review, we discuss the substantial research progress in different aspects of synaptic and molecular changes that can shed light on the mechanism of synaptic dysfunction in FASD. Increasing our understanding of the synaptic changes in FASD will significantly advance our knowledge and could provide a basis for finding novel therapeutic targets and innovative treatment strategies.

The actions of cannabis are mediated by G protein-coupled receptors that are part of an endogenous cannabinoid system (ECS). ECS consists of the naturally occurring ligands N-arachidonylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB₁ and CB₂ cannabinoid receptors. Epigenetics are heritable changes that affect gene expression without changing the DNA sequence, transducing external stimuli in stable alterations of the DNA or chromatin structure. Cannabinoid receptors are crucial candidates for exploring their functions through epigenetic approaches due to their significant roles in health and diseases. Epigenetic changes usually promote alterations in the expression of genes and proteins that can be evaluated by various transcriptomic and proteomic analyses. Despite the exponential growth of new evidence on the critical functions of cannabinoid receptors, much is still unknown regarding the contribution of various genetic and epigenetic factors that regulate cannabinoid receptor gene expression. Recent studies have identified several immediate and long-lasting epigenetic changes, such as DNA methylation, DNA-associated histone proteins, and RNA regulatory networks, in cannabinoid receptor function. Thus, they can offer solutions to many cellular, molecular, and behavioral impairments found after modulation of cannabinoid receptor activities. In this review, we discuss the significant research advances in different epigenetic factors contributing to the regulation of cannabinoid receptors and their functions under both physiological and pathological conditions. Increasing our understanding of the epigenetics of cannabinoid receptors will significantly advance our knowledge and could lead to the identification of novel therapeutic targets and innovative treatment strategies for diseases associated with altered cannabinoid receptor functions.

An embryo’s in-utero exposure to ethanol due to a mother’s alcohol drinking results in a range of deficits in the child that are collectively termed fetal alcohol spectrum disorders (FASDs). Prenatal ethanol exposure is one of the leading causes of preventable intellectual disability. Its neurobehavioral underpinnings warrant systematic research. We investigated the immediate effects on embryos of acute prenatal ethanol exposure during gestational days (GDs) and the influence of such exposure on persistent neurobehavioral deficits in adult offspring. We administered pregnant C57BL/6J mice with ethanol (1.75 g/kg) (GDE) or saline (GDS) intraperitoneally (i.p.) at 0 h and again at 2 h intervals on GD 8 and GD 12. Subsequently, we assessed apoptosis, differentiation, and signaling events in embryo forebrains (E13.5; GD13.5). Long-lasting effects of GDE were evaluated via a behavioral test battery. We also determined the long-term potentiation and synaptic plasticity-related protein expression in adult hippocampal tissue. GDE caused apoptosis, inhibited differentiation, and reduced pERK and pCREB signaling and the expression of transcription factors Pax6 and Lhx2. GDE caused persistent spatial and social investigation memory deficits compared with saline controls, regardless of sex. Interestingly, GDE adult mice exhibited enhanced repetitive and anxiety-like behavior, irrespective of sex. GDE reduced synaptic plasticity-related protein expression and caused hippocampal synaptic plasticity (LTP and LTD) deficits in adult offspring. These findings demonstrate that binge-like ethanol exposure at the GD8 and GD12 developmental stages causes defects in pERK–pCREB signaling and reduces the expression of Pax6 and Lhx2, leading to impaired cellular differentiation during the embryonic stage. In the adult stage, binge-like ethanol exposure caused persistent synaptic and behavioral abnormalities in adult mice. Furthermore, the findings suggest that combining ethanol exposure at two sensitive stages (GD8 and GD12) causes deficits in synaptic plasticity-associated proteins (Arc, Egr1, Fgf1, GluR1, and GluN1), leading to persistent FASD-like neurobehavioral deficits in mice.