Biology subjects

Madhavan, L.

Publications and source records attributed to Madhavan, L..

6 recordsLinked to original sources

bioRxiv2026

Neuroprotective activity of sub-anesthetic ketamine in a preclinical model of Parkinson's disease is not blocked by antagonizing brain-derived neurotrophic factor signaling

Treatment with low-dose ketamine is neuroprotective in rodent models of acute damage, while high doses of ketamine can be neurotoxic. Our group has previously shown that sub-anesthetic ketamine treatment leads to long-term reduction of L-DOPA-induced dyskinesia (LID) via brain-derived neurotrophic factor (BDNF)-signaling in a rat 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). In this report, we investigated if sub-anesthetic ketamine is also neuroprotective in a progressive 6-OHDA model of PD via neurotrophic action through the tropomyosin receptor kinase B (TrkB) receptor. We demonstrated that ketamine-treatment (20 mg/kg, i.p.) prior to striatal administration of the neurotoxin 6-OHDA is neuroprotective, providing near complete protection against development of parkinsonian motor deficits. This robust behavioral efficacy occurred in the presence of only modest preservation of tyrosine hydroxylase (TH) striatal levels (~50-60% loss). Interestingly, based on data from an additional cohort treated with ketamine and ANA-12 (TrkB antagonist) we found that the neuroprotective effects of ketamine are not mediated by TrkB receptors. Semi-quantitative western analysis showed that the relative tyrosine hydroxylase content in the striatum was not significantly increased in ketamine-treated rats compared to vehicle. Unbiased stereology of dopamine neurons in the substantia nigra pars compacta (SNc) revealed no significant differences between any of the groups. The role of BDNF was evaluated with in situ hybridization for RNA of BDNF and TrkB. While BDNF expression was not changed, co-administration of ketamine and ANA-12 led to a significant decrease in TrkB receptor expression compared to ketamine-only on the lesioned but not the intact hemisphere in the SNc. In conclusion, we show that ketamine at the low dose currently pursued for therapeutic benefit for LID led to robust behavioral motor improvement in this rodent PD degeneration model, yet these protective effects were not driven by neurotrophic BDNF-signaling, indicating complex mechanisms are underlying neuroprotective activities of low-dose ketamine.

neuroscience↗

bioRxiv2025

Bioenergetic and Protein Processing Imbalances Synergize in iPSC-Dopamine neurons from Individuals with Idiopathic Parkinsons Disease

Patient induced pluripotent stem cell (iPSC)-based models represent a powerful human system to gain insights into the etiopathology of Parkinsons disease (PD). Here, we study several iPSC-derived dopamine neuron (iPSC-DAN) lines, from individuals with idiopathic PD, which is the most common form of PD. Specifically, using iPSC-DAN differentiated for 50-55 days, we performed an in-depth analysis of different bioenergetic pathways and cellular quality control mechanisms in the cells. Our results showed wide ranging impairments in oxidative phosphorylation (OXPHOS), glycolysis and creatine kinase pathways in the PD dopamine (DA) neurons. Specifically, the PD neurons exhibited reduced oxygen consumption rates (OCR) at baseline and after challenges with mitochondrial inhibitors, as well as decreased glycolytic reserves measured via ECAR. This translated to lower OCR:ECAR ratios signifying more reliance on glycolysis vs OXPHOS in the PD cells. Moreover, a mislocalization of creatine kinase B to mitochondria was seen in the PD cells. These energetic changes synergized with the enhanced expression of mitochondrial fission proteins, disrupted mitophagy and oxidative stress. Additionally, the PD neurons contained more monomeric, phosphorylated and aggregated forms of alpha synuclein and displayed reduced viability. Ultrastructural examination through immuno-electron microscopy showed more alpha synuclein gold particles directly associated with mitochondria and packing autophagic vesicles. In essence, these data capture a web of key changes in human iPSC-DAN from idiopathic PD subjects associated with neuronal degeneration.

neuroscience↗

bioRxiv2025

Acute E2/P4 loss compromises the biology and function of neurogenic niches during a vulnerable female aging period

Effects of aging on neural stem progenitor cells (NSPCs) have been studied in males, but less is known in females. Here we comparatively assess female NSPC biology, both in the subventricular zone and hippocampal dentate gyrus niches, across different ages of F344 rats (2, 6, 9 and 14 months). The rats were ovariectomized (OVX) or remained Intact at each of the aging stages, to assess the role of the female sex hormones, estradiol (E2) and progesterone (P4). Results show that while age-dependent decays become prominent at 14 months, ovariectomy-induced E2/P4 loss markedly reduces neurogenesis and associated behavioral function, earlier, at 9 months of age. Coinciding with this pattern of neurogenic decline, we also detect adaptive changes in estrogen and progesterone receptor expression, antioxidant expression, and brain E2/P4 levels. Fundamentally, these results reveal specific female time-periods, when the brain is sensitive to age and E2/P4 loss, potentially setting-up for disease susceptibility.

neuroscience↗

bioRxiv2025

The 5-HT1F Receptor Agonist Lasmiditan improves Cognition and Ameliorates Associated Cortico-Hippocampal Pathology in Aging Parkinsonian Mice

While the etiopathology of Parkinsons disease (PD) is complex, mitochondrial dysfunction is established to have a central role. Thus, mitochondria have emerged as targets of therapeutic interventions aiming to slow or modify PD progression. We have previously identified serotonergic 5-HT1F receptors as novel mediators of mitochondrial biogenesis (MB) - the process of producing new mitochondria. Given this, here, we assessed the therapeutic potential of the FDA-approved 5-HT1F receptor agonist, lasmiditan, in a chronic progressive PD model (Thy1-aSyn line 61 mice). It was observed that systemic lasmiditan exhibited robust brain penetration and reversed cognitive deficits in young (4-5.5 months old) Thy1-aSyn mice (1mg/kg, every other day). Anxiety-like behavior was also improved while motor function remained unaffected. These behavioral changes were associated with enhanced MB and mitochondrial function, paired with reduced alpha-synuclein aggregation particularly in cortico-hippocampal regions. Furthermore, in older (10-11.5 months old) mice, although the effects were milder, daily lasmiditan administration increased MB and bettered cognitive abilities. In essence, these findings indicate that repurposing lasmiditan could be a potent strategy to address PD-related cognitive decline.

neuroscience↗

bioRxiv2023

Parallel Neurodegenerative Phenotypes in Sporadic Parkinsons Disease Fibroblasts and Midbrain Dopamine Neurons

Understanding the mechanisms causing Parkinsons disease (PD) is vital to the development of much needed early diagnostics and therapeutics for this debilitating condition. Here, we report cellular and molecular alterations in skin fibroblasts of late-onset sporadic PD subjects, that were recapitulated in matched induced pluripotent stem cell (iPSC)-derived midbrain dopamine (DA) neurons, reprogrammed from the same fibroblasts. Specific changes in growth, morphology, reactive oxygen species levels, mitochondrial function, and autophagy, were seen in both the PD fibroblasts and DA neurons, as compared to their respective controls. Additionally, significant alterations in alpha synuclein expression and electrical activity were also noted in the PD DA neurons. Interestingly, although the fibroblast and neuronal phenotypes were similar to each other, they also differed in their nature and scale. Furthermore, statistical analysis revealed novel associations between various clinical measures of the PD subjects and the different fibroblast and neuronal data. In essence, these findings encapsulate spontaneous, in-tandem, disease-related phenotypes in both sporadic PD fibroblasts and iPSC-based DA neurons, from the same patient, and generates an innovative model to investigate PD mechanisms with a view towards rational disease stratification and precision treatments.

neuroscience↗

bioRxiv2022

α-synuclein over expression, NRF2 suppression, and enhanced ferroptosis creates a vicious cycle of neuronal loss in Parkinson's disease

Parkinsons disease (PD) is the second most common neurodegenerative disorder, affecting millions each year. Most PD cases ([~]90%) are sporadic, resulting from the age-dependent accumulation of pathogenic effects. One key pathological hallmark of PD progression is the accumulation of alpha-synuclein (-syn), which has been shown to negatively affect neuronal function and viability. Here, using 3- and 6-month-old Nrf2+/+ and Nrf2-/- mice overexpressing human -syn (PD model), we show that loss of NRF2 increases markers of ferroptosis across PD-relevant brain regions. Increased ferroptosis was associated with an age- and genotype-dependent increase in -syn pathology and behavioral deficits. Finally, we demonstrate that -syn overexpression sensitizes neuronal cells and ex vivo brain slices to ferroptosis induction, which may be due to -syn suppression of NRF2 at the protein level. Altogether, these results indicate that NRF2 is a critical anti-ferroptotic mediator of neuronal survival, and that the vicious cycle of -syn overexpression and NRF2 suppression, leading to enhanced neuronal ferroptotic cell death, could represent a targetable and currently untapped means of preventing PD onset and progression.

neuroscience↗