Advances in Gene Therapy Approaches Targeting Neuro-inflammation in Neurodegenerative Diseases.

Over the last three decades, neurodegenerative diseases (NDs) have increased in frequency. About 15% of the world's population suffers from NDs in some capacity, which causes cognitive and physical impairment. Neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Parkinson's disease, Alzheimer's disease, and others represent a significant and growing global health challenge. Neuroinflammation is recognized to be related to all NDs, even though NDs are caused by a complex mix of genetic, environmental, and lifestyle factors. Numerous genes and pathways such as NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. In AD, the binding of Aß with CD36, TLR4, and TLR6 receptors results in activation of microglia which start to produce proinflammatory cytokines and chemokines. Consequently, the pro-inflammatory cytokines worsen and spread neuroinflammation, causing the deterioration of healthy neurons and the impairment of brain functions. Gene therapy has emerged as a promising therapeutic approach to modulate the inflammatory response in NDs, offering potential neuroprotective effects and disease-modifying benefits. This review article focuses on recent advances in gene therapy strategies targeting neuroinflammation pathways in NDs. We discussed the molecular pathways involved in neuroinflammation, highlighted key genes and proteins implicated in these processes, and reviewed the latest preclinical and clinical studies utilizing gene therapy to modulate neuroinflammatory responses. Additionally, this review addressed the prospects and challenges in translating gene therapy approaches into effective treatments for NDs.

Acetyl-11-keto-beta boswellic acid(AKBA) modulates CSTC-pathway by activating SIRT-1/Nrf2-HO-1 signalling in experimental rat model of obsessive-compulsive disorder: Evidenced by CSF, blood plasma and histopathological alterations.

Obsessive-Compulsive disorder (OCD) is a long-term and persistent mental illness characterised by obsessive thoughts and compulsive behaviours. Numerous factors can contribute to the development or progression of OCD. These factors may result from the dysregulation of multiple intrinsic cellular pathways, including SIRT-1, Nrf2, and HO-1. Inhibitors of selective serotonin reuptake (SSRIs) are effective first-line treatments for OCD. In our ongoing research, we have investigated the role of SIRT-1, Nrf2, and HO-1, as well as the neuroprotective potential of Acetyl-11-keto-beta boswellic acid (AKBA) against behavioural and neurochemical changes in rodents treated with 8-OH-DPAT. In addition, the effects of AKBA were compared to those of fluvoxamine (FLX), a standard OCD medication. Injections of 8-OH-DPAT into the intra-dorso raphe nuclei (IDRN) of rats for seven days induced repetitive and compulsive behaviour accompanied by elevated oxidative stress, inflammatory processes, apoptosis, and neurotransmitter imbalances in CSF, blood plasma, and brain samples. Chronic administration of AKBA at 50 mg/kg and 100 mg/kg p.o. restored histopathological alterations in the cortico-striatal-thalamo-cortical (CSTC) pathway, including the cerebral cortex, striatum, and hippocampal regions. Our investigation revealed that when AKBA and fluvoxamine were administered together, the alterations were restored to a greater degree than when administered separately. These findings demonstrate that the neuroprotective effect of AKBA can serve as an effective basis for developing a novel OCD treatment.

Activating SIRT-1 Signalling with the Mitochondrial-CoQ10 Activator Solanesol Improves Neurobehavioral and Neurochemical Defects in Ouabain-Induced Experimental Model of Bipolar Disorder.

Bipolar disorder (BD) is a chronic mental illness characterized by mood fluctuations that range from depressive lows to manic highs. Several studies have linked the downregulation of SIRT-1 (silent mating type information regulation-2 homologs) signaling to the onset of BD and other neurological dysfunctions. This research aimed to look into the neuroprotective potential of Solanesol (SNL) in rats given ICV-Ouabain injections, focusing on its effect on SIRT-1 signaling activation in the brain. Ouabain, found in hypothalamic and medullary neurons, is an endogenous inhibitor of brain Na+/K+ ATPase. The inhibition of brain Na+/K+ ATPase by Ouabain may also result in changes in neurotransmission within the central nervous system. SNL is a Solanaceae family active phytoconstituent produced from the plant Nicotiana tabacum. SNL is used as a precursor for the production of CoQ10 (Coenzyme Q10), a powerful antioxidant and neuroprotective compound. In the current study, lithium (Li), an important mood stabilizer drug, was used as a control. This study looked at the neuroprotective potential of SNL at dosages of 40 and 80 mg/kg in ICV-OUA injections that caused BD-like neurobehavioral and neurochemical defects in Wistar rats. Wistar rats were placed into eight groups (n = 6) and administered 1 mM/0.5 µL ICV-OUA injections for three days. Neurochemical assessments were done in rat brain homogenates, CSF, and blood plasma samples at the end of the experiment protocol schedule. Long-term SNL and lithium administration have been shown to decrease the number of rearing and crossings and reduce time spent in the center, locomotor activities, and immobility time. Solansesol treatment gradually raises the amount of Na+/K+ ATPase, limiting the severity of behavioural symptoms. These findings also revealed that SNL increases the levels of SIRT-1 in CSF, blood plasma, and brain homogenate samples. Moreover, in rat brain homogenates and blood plasma samples, SNL modulates apoptotic markers such as Caspase-3, Bax (pro-apoptotic), and Bcl-2 (anti-apoptotic). Mitochondrial-ETC complex enzymes, including complex-I, II, IV, V, and CoQ10, were also restored following long-term SNL treatment. Furthermore, SNL lowered inflammatory cytokines (TNF-α, IL-1ß) levels while restoring neurotransmitter levels (serotonin, dopamine, glutamate, and acetylcholine) and decreasing oxidative stress markers. Histological examinations also validated Solanesol's protective effect. As a result, our findings suggest that SNL, as a SIRT-1 signalling activator, may be a promising therapeutic approach for BD-like neurological dysfunctions.

Nrf2/HO-1 Signaling Stimulation through Acetyl-11-Keto-Beta-Boswellic Acid (AKBA) Provides Neuroprotection in Ethidium Bromide-Induced Experimental Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a severe immune-mediated neurological disease characterized by neuroinflammation, demyelination, and axonal degeneration in the central nervous system (CNS). This is frequently linked to motor abnormalities and cognitive impairments. The pathophysiological hallmarks of MS include inflammatory demyelination, axonal injury, white matter degeneration, and the development of CNS lesions that result in severe neuronal degeneration. Several studies suggested downregulation of nuclear factor erythroid-2-related factor-2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling is a causative factor for MS pathogenesis. Acetyl-11-keto-ß-boswellic acid (AKBA) is an active pentacyclictriterpenoid obtained from Boswellia serrata, possessing antioxidant and anti-inflammatory properties. The present study explores the protective potential of AKBA on behavioral, molecular, neurochemical, and gross pathological abnormalitiesandhistopathological alterations by H&E and LFB staining techniques in an experimental model of multiple sclerosis, emphasizing the increase inNrf2/HO-1 levels in the brain. Moreover, we also examine the effect of AKBA on the intensity of myelin basic protein (MBP) in CSF and rat brain homogenate. Specific apoptotic markers (Bcl-2, Bax, andcaspase-3) were also estimated in rat brain homogenate. Neuro behavioralabnormalities in rats were examined using an actophotometer, rotarod test, beam crossing task (BCT),and Morris water maze (MWM). AKBA 50 mg/kg and 100 mg/kg were given orally from day 8 to 35 to alleviate MS symptoms in the EB-injected rats. Furthermore, cellular, molecular, neurotransmitter, neuroinflammatory cytokine, and oxidative stress markers in rat whole brain homogenate, blood plasma, and cerebral spinal fluid were investigated. This study shows that AKBA upregulates the level of antioxidant proteins such as Nrf2 and HO-1 in the rat brain. AKBA restores altered neurochemical levels, potentially preventing gross pathological abnormalities during MS progression.

Activation of IGF-1/GLP-1 Signalling via 4-Hydroxyisoleucine Prevents Motor Neuron Impairments in Experimental ALS-Rats Exposed to Methylmercury-Induced Neurotoxicity.

Amyotrophic lateral sclerosis (ALS) is a severe adult motor neuron disease that causes progressive neuromuscular atrophy, muscle wasting, weakness, and depressive-like symptoms. Our previous research suggests that mercury levels are directly associated with ALS progression. MeHg+-induced ALS is characterised by oligodendrocyte destruction, myelin basic protein (MBP) depletion, and white matter degeneration, leading to demyelination and motor neuron death. The selection of MeHg+ as a potential neurotoxicant is based on our evidence that it has been connected to the development of ALS-like characteristics. It causes glutamate-mediated excitotoxicity, calcium-dependent neurotoxicity, and an ALS-like phenotype. Dysregulation of IGF-1/GLP-1 signalling has been associated with ALS progression. The bioactive amino acid 4-hydroxyisoleucine (HI) from Trigonella foenum graecum acts as an insulin mimic in rodents and increases insulin sensitivity. This study examined the neuroprotective effects of 4-HI on MeHg+-treated adult Wistar rats with ALS-like symptoms, emphasising brain IGF1/GLP-1 activation. Furthermore, we investigated the effect of 4-HI on MBP levels in rat brain homogenate, cerebrospinal fluid (CSF), blood plasma, and cell death indicators such as caspase-3, Bax, and Bcl-2. Rats were assessed for muscular strength, locomotor deficits, depressed behaviour, and spatial learning in the Morris water maze (MWM) to measure neurobehavioral abnormalities. Doses of 4-HI were given orally for 42 days in the MeHg+ rat model at 50 mg/kg or 100 mg/kg to ameliorate ALS-like neurological dysfunctions. Additionally, neurotransmitters and oxidative stress markers were examined in rat brain homogenates. Our findings suggest that 4-HI has neuroprotective benefits in reducing MeHg+-induced behavioural, neurochemical, and histopathological abnormalities in ALS-like rats exposed to methylmercury.

Role of JAK-STAT and PPAR-Gamma Signalling Modulators in the Prevention of Autism and Neurological Dysfunctions.

The Janus-kinase (JAK) and signal transducer activator of transcription (STAT) signalling pathways regulate gene expression and control various factors involved in normal physiological functions such as cell proliferation, neuronal development, and cell survival. JAK activation phosphorylates STAT3 in astrocytes and microglia, and this phosphorylation has been linked to mitochondrial damage, apoptosis, neuroinflammation, reactive astrogliosis, and genetic mutations. As a regulator, peroxisome proliferator-activated receptor gamma (PPAR-gamma), in relation to JAK-STAT signalling, prevents this phosphorylation and aids in the treatment of the above-mentioned neurocomplications. Changes in cellular signalling may also contribute to the onset and progression of autism. Thus, PPAR-gamma agonist upregulation may be associated with JAK-STAT signal transduction downregulation. It may also be responsible for attenuating neuropathological changes by stimulating SOCS3 or involving RXR or SMRT, thereby reducing transcription of the various cytokine proteins and genes involved in neuronal damage. Along with JAK-STAT inhibitors, PPAR-gamma agonists could be used as target therapeutic interventions for autism. This research-based review explores the potential involvement and mutual regulation of JAK-STAT and PPAR-gamma signalling in controlling multiple pathological factors associated with autism.

Smo-Shh Agonist Purmorphamine Prevents Neurobehavioral and Neurochemical Defects in 8-OH-DPAT-Induced Experimental Model of Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder is a mental disorder characterized by repetitive, unwanted thoughts and behavior due to abnormal neuronal corticostriatal-thalamocortical pathway and other neurochemical changes. Purmorphamine is a smoothened-sonic-hedgehog agonist that has a protective effect against many neurological diseases due to its role in maintaining functional connectivity during CNS development and its anti-inflammatory and antioxidant properties. As part of our current research, we investigated the neuroprotective effects of PUR against behavioral and neurochemical changes in 8-hydroxy-2-(di-n-propylamino)-tetralin-induced obsessive-compulsive disorder in rats. Additionally, the effect of PUR was compared with the standard drug for OCD, i.e., fluvoxamine. The intra-dorsal raphe-nucleus injection of 8-OH-DPAT in rats for seven days significantly showed OCD-like repetitive and compulsive behavior along with increased oxidative stress, inflammation, apoptosis, as well as neurotransmitter imbalance. These alterations were dose-dependently attenuated by long-term purmorphamine treatment at 5 mg/kg and 10 mg/kg i.p. In this study, we assessed the level of various neurochemical parameters in different biological samples, including brain homogenate, blood plasma, and CSF, to check the drug's effect centrally and peripherally. These effects were comparable to the standard oral treatment withfluvoxamine at 10 mg/kg. However, when fluvoxamine was given in combination with purmorphamine, there was a more significant restoration of these alterations than the individualtreatmentswithfluvoxamine and purmorphamine. All the above findings demonstrate that the neuroprotective effect of purmorphamine in OCD can be strong evidence for developing a new therapeutic target for treating and managing OCD.

Activation of SIRT-1 Signalling in the Prevention of Bipolar Disorder and Related Neurocomplications: Target Activators and Influences on Neurological Dysfunctions.

SIRT-1 (silent mating-type information regulation 2 homolog-1) is a protein found in neuronal nuclei, microglia, and astrocyte cells of the brain. It is sometimes referred to as NAD + -dependent deacetylase (nicotinamide adenine dinucleotide). The activation of sirtuins (SIRT-1-7) has been shown to protect against a wide range of disorders, including neurodegenerative and neuropsychiatric disorders. SIRT-1 has gained considerable interest from these families because of its early link to long-life expansion and calorie restriction involvement. SIRT-1 is necessary for gene silencing, cell cycle regulation, fat and glucose metabolism, oxidative stress, ageing, and memory formation. In this review, we investigate the role of SIRT-1 downregulation in the progression of bipolar disorder (BD) and neurological abnormalities, as well as related neurological alterations such as genetic dysfunction, neurotransmitter imbalance, oxidative stress-induced apoptosis, and mitochondrial dysfunction. BD is a psychiatric disease distinguished by extreme mood fluctuations that range from depressive lows to manic highs. BD is a complicated disorder with numerous clinical signs and neurocomplications that produce significant behavioural problems. SIRT-1 deficiency in the brain has been demonstrated to affect the activity of its transcription factors and molecular changes, including genetic defects. SIRT-1 is now being studied as a potential therapeutic target for a range of brain disorders. A recent study also found that activating SIRT-1 signalling performs a protective effect in avoiding depression and mania-like behaviours. Furthermore, this review investigates the potential mechanisms by which SIRT-1 regulates neuronal transmission and neurogenesis. As a result of our review, we revealed that SIRT-1 activators have neuroprotective potential in BD and related neurological dysfunctions.