golexanolone (GR3027) / Karolinska Development - LARVOL DELTA

Golexanolone Attenuates Neuroinflammation, Fatigue, and Cognitive and Motor Impairment in Diverse Neuroinflammatory Disorders. (PubMed, Pharmaceuticals (Basel)) - "Golexanolone also normalizes elevated levels of α-synuclein. These findings suggest that golexanolone has beneficial therapeutic effects for treating fatigue, depression, motor, and cognitive impairment across diverse neuroinflammatory conditions, including synucleinopathies."

Journal • Review • Alzheimer's Disease • Cholestasis • CNS Disorders • Cognitive Disorders • Depression • Fatigue • Hepatic Encephalopathy • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Mood Disorders • Movement Disorders • Parkinson's Disease • Primary Biliary Cholangitis • Psychiatry

Sez6L2 regulates synaptic connectivity by inhibiting complement-mediated pruning during neurodevelopment (Neuroscience 2025) - "Grant Support NIH Grant GR530272; Grant Support NIH Grant T32NS115705 Sez6L2 is a neuron-specific protein that our lab has identified as a novel inhibitor of complement deposition in vitro...Finally, we show that postnatal day 10 (P10) Sez6L2 KO mice have decreased synaptic density in the lateral geniculate nucleus (LGN). Overall, our data have implications for the important role of Sez6L2 in modulating complement activity during key neurodevelopmental periods, leading to aberrant complement-mediated synaptic pruning and abnormal brain development."

CNS Disorders • Psychiatry

Golexanolone affords sustained improvement of Parkinson's symptoms in rats by reducing microglia activation that restores the glutamate-GABA-dopamine pathway. (PubMed, Neuropharmacology) - "Early treatment affords more beneficial effects than late treatment on PD symptoms. Golexanolone affords sustained improvement of PD symptoms in the rat model by reducing neuroinflammation, increasing dopaminergic signalling and therefore could be considered for clinical evaluation in patients with PD."

Journal • Preclinical • CNS Disorders • Fatigue • Inflammation • Movement Disorders • Parkinson's Disease

An update on novel investigational agents for the treatment of primary biliary cholangitis. (PubMed, Expert Opin Investig Drugs) - "While ursodeoxycholic acid (UDCA) remains the first-line treatment, up to 40% of patients show an inadequate response...Obeticholic acid (OCA), a farnesoid X receptor agonist, was initially approved but recently lost its marketing authorization in the EU due to an unfavorable risk-benefit balance. Fibrates, particularly bezafibrate and fenofibrate, have shown promising results in improving biochemical markers and reducing pruritus, although they remain off-label. We here focus on new FDA- and EMA-approved therapies, including the PPAR agonists elafibranor and seladelpar, which demonstrate improved biochemical response and, in the case of seladelpar, a significant reduction in pruritus. Additional investigational agents include NOX inhibitors such as setanaxib, IBAT inhibitors like linerixibat and odevixibat, and golexanolone, targeting fatigue through modulation of GABAergic neurotransmission. Despite advances, challenges remain in treatment personalization, access to..."

Journal • Review • Dermatology • Fatigue • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Primary Biliary Cholangitis • Pruritus

Golexanolone affords sustained microglia and astrocytes activation improvement in a rat model of Parkinson's disease. (PubMed, Front Immunol) - "Golexanolone reversed microglia activation, the increase in pro-inflammatory factors and astrocytes A1 activation both at 3 and 9 weeks. Sustained improvement of glial activation in SN and striatum would be a key mechanism in the improvement of PD symptoms by golexanolone."

Journal • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • GFAP • HMGB1 • S100A10 • S100B • TNFA • VIM

REG-Karolinska Development’s portfolio company Umecrine Cognition receives grant from The Michael J. Fox Foundation (TradingView) - "Karolinska Development AB...announces that its portfolio company Umecrine Cognition has been awarded a research grant by The Michael J. Fox Foundation (MJFF) amounting to USD 420,000. The grant will finance preclinical studies to evaluate the potential treatment effect of golexanolone in Parkinson’s disease....The grant is awarded to the collaboration between Umecrine Cognition and the principal investigator, Professor Gilberto Fisone Head of the Laboratory of Molecular and Circuit Neuropharmacology, and Chair of the Department of Neuroscience, at Karolinska Institutet, Solna, Sweden."

Financing • Parkinson's Disease

Karolinska Development’s portfolio company Umecrine Cognition presents promising preclinical Parkinson data at AD/PD 2025 (GlobeNewswire) - "Karolinska Development AB...today announces that its portfolio company Umecrine Cognition presents recent preclinical data showing that golexanolone reverses dopamine loss and sustains improvements of Parkinsonian symptoms at the 19th International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD) 2025, in Vienna, Austria, April 1–5th....The results from the study increase the understanding of golexanolone’s mechanism of action and support further development of the drug candidate as a potential treatment for Parkinson’s disease."

Preclinical • Parkinson's Disease

GOLEXANOLONE IMPROVES THE MECHANISMS IN SUBSTANTIA NIGRA LEADING TO STRIATAL DOPAMINE LOSS AND MOTOR AND NON -MOTOR ALTERATIONS IN 6 -OHDA RATS (ADPD 2025) - "Golexanolone improves the mechanisms leading to dopamine loss and motor and non -motor deficits in 6 -OHDA rats and may induce similar beneficial effects in patients with Parkinson's disease. (1) Izquierdo -Altarejos et al. Front Aging Neurosci."

Preclinical • CNS Disorders • Fatigue • Movement Disorders • Parkinson's Disease • GFAP

Karolinska Development’s portfolio company Umecrine Cognition presents new preclinical Parkinson’s data on golexanolone at the scientific conference, INBC 2024 (GlobeNewswire) - "The results from the preclinical study that will be presented at INBC 2024 showed that treatment with Umecrine Cognitions’ clinical drug candidate golexanolone significantly reduced the decrease of a dopamine-producing enzyme in the brain and returned dopamine to normal levels. The study also showed that an early onset of treatment generated sustained effects, indicating a potential for reduced symptomatic progression."

Preclinical • CNS Disorders • Parkinson's Disease

Golexanolone reduces glial activation in the striatum and improves non-motor and some motor alterations in a rat model of Parkinson's disease. (PubMed, Front Aging Neurosci) - "Notably, golexanolone reduced the activation of microglia and astrocytes, mitigated TH loss at 5 weeks after surgery, and prevented the increase of α-synuclein levels at 10 weeks. Golexanolone may be useful in improving both motor and non-motor symptoms that adversely affect the quality of life in PD patients, such as anxiety, depression, fatigue, motor coordination, locomotor gait, and certain cognitive alterations."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Fatigue • Movement Disorders • Parkinson's Disease • Psychiatry

Allopregnanolone And Its Antagonist Modulate Neuroinflammation And Neurological Impairment. (PubMed, Neurosci Biobehav Rev) - "What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease."

Journal • Review • CNS Disorders • Cognitive Disorders • Developmental Disorders • Hepatology • Inflammation

Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination. Mechanisms and therapeutic implications. (PubMed, Front Pharmacol) - "Golexanolone reduces neuroinflammation and GABAergic neurotransmission in animal models of hyperammonemia, hepatic encephalopathy and cholestasis and this is associated with improvement of fatigue, cognitive impairment and motor incoordination. This type of compounds may be useful therapeutic tools to improve cognitive and motor function in different pathologies associated with neuroinflammation and increased GABAergic neurotransmission."

Journal • Review • Alzheimer's Disease • Cholestasis • CNS Disorders • Cognitive Disorders • Fatigue • Hepatic Encephalopathy • Hepatology • Inflammation • Movement Disorders • Parkinson's Disease • BDNF • CCL2 • TNFA • TNFRSF1A

GOLEXANOLONE, A GABAA RECEPTOR-MODULATING STEROID ANTAGONIST, IMPROVES FATIGUE, ANXIETY, DEPRESSION AND SOME COGNITIVE AND MOTOR ALTERATIONS IN 6- OHDA RATS (ADPD 2024) - "Golexanolone treatment may be useful to improve different symptoms that affect the patients' quality of life: anxiety, depression, fatigue, some aspects of motor coordination and locomotor gait, and some cognitive alterations. These beneficial effects would be due to a reduction of GABAergic neurotransmission and neuroinflammation."

Preclinical • CNS Disorders • Depression • Fatigue • Inflammation • Movement Disorders • Parkinson's Disease • Psychiatry

The golexanolone improvement the inflammation peripheral, the fatigue, the March locomotive, the incoordination motorboat and the memory to short term in rats with cholestasis andencephalopathy hepatic due to ligature of the ducts biliary (AEEH 2024) - No abstract available

Preclinical • Cholestasis • CNS Disorders • Fatigue • Hepatic Encephalopathy • Hepatology • Inflammation

Hepatic encephalopathy: investigational drugs in preclinical and early phase development. (PubMed, Expert Opin Investig Drugs) - "Current treatments are lactulose or rifaximin, acting on gut microbiota...HE may be reversed using drugs acting at any step: modulating microbiota with probiotics or fecal transplantation; reducing peripheral inflammation with anti-TNFα, autotaxin inhibitors or silymarin; reducing neuroinflammation with sulforaphane, p38 MAP kinase or phosphodiesteras 5 inhibitors, antagonists of sphingosine-1-phosphate receptor 2, enhancing meningeal lymphatic drainage or with extracellular vesicles from mesenchymal stem cells; reducing GABAergic neurotransmission with indomethacin or golexanolone...Only drugs acting on microbiota or ammonia reduction have been tested in patients. t is urgent to change the mentality on how to approach HE treatment to develop clinical trials to assess drugs acting on the immune system/peripheral inflammation, neuroinflammation or neurotransmission to improve HE."

Journal • Preclinical • Review • CNS Disorders • Hepatic Encephalopathy • Hepatology • Inflammation • Liver Failure • Psychiatry • Transplantation

Golexanolone improves fatigue, motor incoordination and gait and memory in rats with bile duct ligation. (PubMed, Liver Int) - "Golexanolone may have beneficial effects to treat fatigue, and motor and cognitive impairment in patients with the chronic cholestatic liver disease PBC."

Journal • Preclinical • Alzheimer's Disease • Cholestasis • Cognitive Disorders • Fatigue • Hepatology • Immunology • Inflammation • Primary Biliary Cholangitis

Extra-Synaptic GABA Receptor Potentiation and Neurosteroid-Induced Learning Deficits Are Inhibited by GR3027, a GABA Modulating Steroid Antagonist. (PubMed, Biomolecules) - "GR3027 treatment did not change other functions in the rat compared to the vehicle group. GR3027 functions in vitro as an inhibitor of GABA receptors holding α5β3γ2L and α1β2γ2L, in vivo, in the rat, as a dose-dependent inhibitor toward AP's negative effects on LoR and learning in the MWM."

Journal • Alzheimer's Disease • Anesthesia • CNS Disorders

Karolinska Development’s portfolio company Umecrine Cognition presents data on golexanolone in a preclinical model of Parkinson’s disease (GlobeNewswire) - "Karolinska Development AB...announces that its portfolio company Umecrine Cognition has presented results from a study on a preclinical model of Parkinson’s disease as a poster at the 6th World Parkinson Congress in Barcelona, July 4-7. The poster shows how the company’s clinical drug candidate golexanolone reverses fatigue, anxiety, depression, and some cognitive and motor alternations in the disease model."

Preclinical • CNS Disorders • Parkinson's Disease

Golexanolone, a GABA receptor-modulating steroid antagonist, improves peripheral inflammation, fatigue, locomotor gait, motor incoordination and short-term memory in rats with cholestasis and hepatic encephalopathy due to bile duct ligation (EASL-ILC 2023) - "Golexanolone reduces peripheral inflammation in BDL rats. This is associated with improvement in fatigue, locomotor gait and coordination, and short-term memory. Golexanolone may have beneficial effects to treat symptomatic alterations such as fatigue, and motor-, and cognitive impairment in patients with cholestatic liver disease, or hepatic encephalopathy"

Preclinical • Alzheimer's Disease • Cholestasis • CNS Disorders • Cognitive Disorders • Fatigue • Hepatic Encephalopathy • Hepatology • Immune Modulation • Inflammation • Liver Failure • Primary Biliary Cholangitis • IL17A • IL18 • IL6 • TNFA

Karolinska Development’s portfolio company Umecrine Cognition presents data on golexanolone’s mode-of-action and ability to reduce neuroinflammation (GlobeNewswire) - "Karolinska Development AB...announces that its portfolio company Umecrine Cognition has announced results from a preclinical model of cholestasis that elucidates the mechanism-of-action of the company’s clinical drug candidate golexanolone in cholestatic liver disease. The results will be presented as a poster during the International Liver Congress EASL in Vienna, June 21-24....The results from the preclinical study showed that golexanolone reversed the increase of several pro-inflammatory interleukins and reversed specific alterations in GABAergic neurotransmission in the cerebellum. Golexanolone also reduced the content of pro-inflammatory factors in the cerebellum."

Preclinical • Cholestasis • Hepatic Encephalopathy • Hepatology • Immunology

GABA-A RECEPTOR MODULATING STEROIDS IMPAIR MEMORY, PROMOTES DEMENTIA, AND ANTAGONIZED BY GABA-A RECEPTOR MODULATING STEROID ANTAGONISTS. (ADPD 2023) - "A GAMSA (golexanolone, GR3027), restored learning and motor coordination in rat models of hepatic encephalopathy... GAMSA seem to be possible to use as treatment for impaired cognition. References: Bengtsson, et al. Neurobi ology of Stress , 2020; 12,100206:1 -20."

Alzheimer's Disease • Anesthesia • CNS Disorders • Cognitive Disorders • Dementia • Fatigue • Hepatic Encephalopathy • Hepatology • Immunology • Inflammation

A two-part study to investigate the effects in adults of two doses of a new drug called golexanolone in patients with primary biliary cholangitis with fatigue and cognitive dysfunction Kétrészes vizsgálat egy új, golexanolon nevű gyógyszer két dózisa hatásainak vizsgálatára kimerültséggel és kognitív diszfunkcióval járó primer biliáris cholangitisben szenvedő felnőtt betegek körében (clinicaltrialsregister.eu) - P1/2 | N=101 | Ongoing | Sponsor: Umecrine Cognition AB

New P1/2 trial • Cognitive Disorders • Fatigue • Hepatology • Immunology • Primary Biliary Cholangitis

Golexanolone, a GABA receptor modulating steroid antagonist, restores motor coordination and cognitive function in hyperammonemic rats by dual effects on peripheral inflammation and neuroinflammation. (PubMed, CNS Neurosci Ther) - "Reducing GABA receptors activation with golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in hyperammonemic rats. The effects identified would also occur in patients with hepatic encephalopathy and, likely, in other pathologies associated with neuroinflammation."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Hepatic Encephalopathy • Hepatology • Immunology • Inflammation • CCL2 • IL10 • NTRK2 • TNFA • TNFRSF1A

Positive GABA receptor modulating steroids and their antagonists: Implications for clinical treatments. (PubMed, J Neuroendocrinol) - "The progesterone metabolite allopregnanolone (Allo) is a positive GABA receptor modulating steroid with potent effects...We have demonstrated that isoallopregnanolone (Isoallo), the 3β-OH sibling of Allo, functions as a GABA receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABA receptors...In humans, vigilance, cognition and pathological electroencephalogram were improved in patients with hepatic encephalopathy on treatment with GR3027. In conclusion GAMSAs are a new possible treatment for disorders and symptoms caused by hyperactivity in the GABA system."

Clinical • Journal • Review • Anesthesia • CNS Disorders • Cognitive Disorders • Depression • Hepatic Encephalopathy • Hepatology • Polycystic Ovary Syndrome

A pilot study of Golexanolone, a new GABA-A receptor modulating steroid antagonist, in patients with covert hepatic encephalopathy. (PubMed, J Hepatol) - P1/2 | "Golexanolone was well tolerated and associated with improvement in cognitive performance. The results implicate GABA-A receptor modulating neurosteroids in the pathogenesis of HE and suggest that golexanolone deserves further study as a potential therapeutic."

Clinical • Journal • CNS Disorders • Cognitive Disorders • Fibrosis • Gastroenterology • Hepatic Encephalopathy • Hepatology • Immunology • Liver Cirrhosis