Eric Konofal1,2, Jean-Charles Bizot 3, Christelle Peyron 4, Fabienne Massé 3, Anne-Laure Morel 4, George Apostol 1
- NLS Pharmaceutics AG, The Circle 6, P.O. Box, CH-8058 Zurich Airport, Switzerland - ek@nls-pharma.com
-
APHP, Hôpital Robert Debré, Centre Pédiatrique des Pathologies du Sommeil, 48 boulevard Sérurier, 75019 Paris, France
3 Key-Obs SAS, 13 avenue Buffon, 45100 Orléans, France
- Centre de Recherche enNeurosciences de Lyon, INSERM U1028, CNRS UMR5292, Lyon 1 University, CH Le Vinatier,Neurocampus MichelJouvet, 95 boulevard Pinel, 69675Bron Cedex, France
Introduction and Rationale
Main Results
Previous experiments have shown that thebilateral infusion of theneurotoxin orexin-B-saporin(OX-B-SAPorHCRT2-SAP), aconjugate of theorexin-Bpeptide and saporin, in thelateral hypothalamus (LH) induced lesions oforexin neurons,producing narcoleptic-likesleepbehavior in rats(Gerashchenkoet al., 2001, 2003).
OX-B-SAP selectively bindsto theorexin-2receptor (OX2R) and lesionsorexin neurons viamicroinjection into the LH, making it avaluabletoolforstudying sleepdisorders.
Aim of the Study
Thisstudy KO-874 aimedto investigate theneuroprotective effects of mazindol on nocturnal activity in arat model with narcoleptic-likesymptoms, induced byOX-B-SAP lesions in thelateralhypothalamus(LH).
Theobjectives were to implement theOX-B-SAPlesion modelat Key-Obs, determine theextent andduration ofcircadianactivitydisruption-particularlythedecrease in activity during the dark phase-andexamine theneuroprotective impact of mazindol on thisdisruption.
The present study shown the neuroprotective effects of mazindol on nocturnal activity in a rat model induced with narcoleptic-like symptoms through the administration of OX-B-SAP lesions in the LH. The main findings are reported Table 2.
- The bilateral infusion of OX-B-SAP (90 ng) into the LH significantly decreased circadian activity, particularly during the dark phase, which effectively modelled the decreased wakefulness seen in narcolepsy. This reduction in activity became significant from the 12th day post-lesion and persisted until the end of the experiment (Day 21).
- Mazindol was administered at 2 doses previously screened (1 mg/kg and 3 mg/kg) to evaluate its therapeutic potential. At a lower dose (1 mg/kg), mazindol showed no therapeutic effect and even appeared to aggravate the reduction in activity between Days 5 and 8 post-lesion.
Table 2. Summary of key findings of all experinents
Parameter | Description and Results |
Lesions caused by OX-B-SAP(orexin-B-saporin) in the | |
lateral hypothalamus led to a significant decrease in | |
OX-B-SAP Lesion | circadian activity from day 12 to day 21 post-lesion. This |
(90 ng) | reduction models the decreased wakefulness seen in |
narcolepsy, indicating effective targeting of orexin- |
Experiment 2.Rats were subdivided into 3 groups which received a bilateral infusion into the LH of either vehicle (Sham-Veh group) or OX-B-SAP (90 ng) (OX-B-SAP-Veh and OX-B-SAP-Maz groups). They received a p.o. administration of either vehicle (0.9% NaCl; Sham-Veh and OX-B-SAP-Veh groups) or 3 mg/kg mazindol (OX-B-SAP- Maz group) immediately after infusion of vehicle or OX-B-SAP and at the beginning of the dark period for 21 consecutive days. Circadian locomotor activity was recorded as described previously (see Figure 2). At the end of the experiment, animals were sacrificed, the brain was collected, frozen in dry ice and transferred to the CNRS- UMR5292 laboratory for histological analysis of orexin neurons in the LH.
Data analysis. OX-B-SAP groups were divided into subgroups according to the extent of the lesion in comparison with the OX-B-SAP-Veh group: High Lesion (HL) groups (OX-B-SAP-Veh HL and OX-B-SAP-Maz HL groups), which showed less than 50% remaining Orexin neurons in the LH, and Low Lesion (LL) groups (OX-B-SAP-Veh LL and OX- B-SAP-Maz LL groups), which showed more than 50% remaining Orexin neurons in the LH (Figure 5).
Sham-vehicle(Sham-Veh) rats showed a higher activity during the dark period than during the light period (Figure 4).
The bilateral infusion of OX-B-SAP (90 ng) induced a decrease in the number of orexin neurons in the LH, which was not significantly modified by mazindol treatment (Figure 5).
The OX-B-SAP infusion induced a decrease in activity in OX-B-SAP-Veh rats (see Figure 4). This
effect:
- was mostly observed during the dark phase,
- was observed only in high-lesion rats (< 50% remaining neurons in the LH), but not in low-lesion rats, and
- began to be significant from Day 12 following lesion and was present until the end of the experiment.
Mazindol mitigated the OX-B-SAP-induced decrease in activity during the dark phase in high-lesion rats (Figure 4), which was:
On Days 6-8,12-15, and 19-21,OX-B-SAP lesioned rats treated with mazindol (3 mg/kg) showed significantly higher activity levels during the dark phase compared to vehicle-treatedOX-B-SAP lesioned rats (Figure 4)
By Day 21, mazindol not only restored the activity levels to normal but exceeded those of the Sham group during the dark phase, indicating a robust protective effect against the activity disruptions caused by the destruction of orexin cells in the LH.
Detailed analysis showed that the beneficial effects of mazindol were more pronounced in rats with less severe lesions (>50% of orexin neurons remaining). These rats exhibited significantly higher activity levels during the dark phase compared to rats with severe lesions (<50% of orexin neurons remaining).
The bilateral infusion of OX-B-SAP induced a significant decrease in the number of orexin neurons in the LH, which was not significantly modified by mazindol treatment (Figure 5).
Mazindol mitigated the OX-B-SAP-induced decrease in activity during the dark phase in high-lesion rats:
- The number of orexin neurons was significantly reduced in the OX-B-SAP treated groups compared to the Sham group.
- The correlation between the number of orexin neurons and the distance traveled during the dark phase was significant in both the OX-B-SAP and OX-B-SAP + Mazindol groups, but not in the Sham group, suggesting that efficacy of mazindol is closely linked to the preservation of orexin neurons.
The analysis by the Pearson r test shows that the correlation between the activity during the dark phase and the number of Orexin neurons in the LH (Figure 6, upper):
- In Sham-Veh group: was far from significant.
- In OX-B-SAP-Veh group: was significant.
- In OX-B-SAP-Maz group: was significant.
There was no significant correlation between the activity during the light phase and the number of orexin neurons (Figure 6, lower) in Sham-Veh and OX-B-SAP-Veh groups, but a close to significant correlation in OX-B-SAP-Maz group.
Methods and Timeline
Animals were housed individually in transparent cages placed in actimeters to continuously record locomotor activity (distance traveled). The distance traveled each day, during dark and light periods, and during each 1-hour period, was recorded over 24-hourperiods duringvarious phases of theexperiment.Normal rats exhibit locomotor activity that is 4-5 times higher during the dark phase than during the light phase.
Narcolepsy symptomatology, induced here by OX-B-SAP lesions in the LH, should be detected by a decrease in activity during the dark phase, without changes during the light phase.
Animals, drugs, andmaterials used in theseexperiments, including the doses andpreparation methods for both OX-B-SAPand mazindol isreported in Table 1.
Timelinesfor experiments 1A, 1B(Figures 1) and 2(Figure 2),highlighted thesurgical procedure, drugadministration, and
activityrecording. Surgicalprocedure in rat andOX-B-SAPadministrationmethod is shown on Figure 3.
Table 1. Animals, drugs and material
Category | Details |
Experiments at Key-Obs by authorized personnel; | |
Compliance with French Ministry of Agriculture guidelines; Approved by Key-Obs SAS Ethical Committee No. 27; | |
General Points | Conducted in standard conditions (T°= 22.0 ± 1.5°C); |
Experiments conducted blindly; | |
No prior experiments on animals. | |
Species: Sprague-Dawley rats, male; Age: 3 weeks at delivery, 5 weeks at surgery, 8 weeks at experiment end; Number: N=75; Origin: | |
Janvier Labs, France; Housing: Single in transparent cages (1290D Eurostandard Type III, Tecniplast); Litter: Aspen Small; Enrichment: | |
Animals | Wood brick; |
producing neurons. | |
At this dosage, mazindol showed no therapeutic effect on | |
the lesion-induced decrease in activity. Interestingly, there | |
Mazindol (1 mg/kg) | was an observed potential aggravation of decreased |
activity between days 5 and 8 post-lesion, suggesting that | |
at lower doses, mazindol might not be effective or could | |
interfere negatively when administered orally. | |
Higher doses of mazindol significantly increased activity on | |
days 5, 12, 14, 20, and 21 post-lesion compared to both | |
sham-operated and OX-B-SAP-only groups. This suggests a | |
dose-dependent effect of mazindol when administered | |
Mazindol (3 mg/kg) | orally, potentially enhancing the orexinergic signaling or |
compensating for the loss of orexin neurons due to the OX- | |
B-SAP lesion. The increase in activity supports the | |
hypothesis that mazindol at higher doses could stimulate | |
the orexin system, which is crucial for maintaining | |
wakefulness and regulating circadian rhythms. | |
In trials where the dosage of OX-B-SAP exceeded 90 ng, | |
administered intraperitoneally (ip), the resultant brain | |
OX-B-SAP Lesion | damage in rats was excessive, extending beyond the initial |
intended lesion area. This extensive damage rendered the | |
(>90 ng, i.p.) | |
results scientifically invalid as the conditions exceeded | |
those of a controlled lesion, affecting the overall brain | |
function and structure beyond the scope of studying | |
targeted orexin neuron disruption. |
- not significantly different between OX-B-SAP-Maz HL rats and Sham-Veh rats during D 6-8, D 12-15 and D 19-21 periods, and
- higher in OX-B-SAP-Maz HL rats than OX-B-SAP-Veh LL rats during the D 19-21 period.
Mazindol-induced increase in activity was more pronounced in low-lesion rats than in high-lesion rats (Figure 4).
Figures 4. Circadian locomotor activity: distance travelled in open-fields during 12-h dark and 12-h light periods of days 6-8,12-15 and 19-21 following surgery.
Sham-Veh (N=10) OX-B-SAP-Veh HL (N=5) | OX-B-SAP-Veh HL (N=2) | OX-B-SAP-Maz HL | OX-B-SAP-Maz LL (N=2) | ||||||
100 000 | ** | ||||||||
+ SEM) | * | ||||||||
80 000 | ** | *** | # | ||||||
mean | # | ||||||||
60 000 | |||||||||
(cm; | |||||||||
* | ** | ||||||||
travelled | 40 000 | * | |||||||
Distance | 20 000 | ||||||||
0 | Dark 0-12 h | Light 12-24h | Dark 0-12 h | Light 12-24h | Dark 0-12 h | Light 12-24h | |||
D 6-8 | D 12-15 | D 19-21 | |||||||
Differences (Student's t-test): vs. Sham-Veh group, * p≤ 0.05; ** p≤ 0.01; *** p≤ 0.001; vs. OX-B-SAP-Veh HL group: # p≤ 0.05. |
Figures 5. Number of orexin neurons in the LH.
✱✱✱✱
ns
SEM)± | 800 | ✱✱✱✱ | |||||||||||
mean | 600 | ||||||||||||
(N; | 400 | LL = Low | |||||||||||
neurons | Lesion | ||||||||||||
200 | HL = High | ||||||||||||
Orexin | Lesion | ||||||||||||
0 | |||||||||||||
Veh | Veh | z | |||||||||||
-Ma | |||||||||||||
ha | - | - | |||||||||||
SAP | S | ||||||||||||
m | P | ||||||||||||
S | - | - | A | ||||||||||
B | B | ||||||||||||
- | - | ||||||||||||
OX | OX |
Difference (Student's t-test): ****p≤ 0.0001
Figures 6. Correlation between the number of Orexin neurons in the LH and the distance travelled during the dark phase (upper) and the light phase (lower) by Sham-Veh (left), OX-B-SAP-Veh (center) and OX-B-SAP Maz (right) rats.
12-h Dark - Sham-Veh - D5-21 | 12-h Dark OX-B-SAP-Veh D5-21 | 12-h Dark OX-B-SAP-MazD5-21 | ||||||||||||||
120 000 | r = 0.535 - p = ns | 120 000 | r = 0.786 - p ≤ 0.05 | 120 000 | r = 0.913 - p ≤ 0.001 | |||||||||||
(cm) | 100 000 | (cm) | 100 000 | (cm) | 100 000 | |||||||||||
80 000 | 80 000 | 80 000 | ||||||||||||||
travelled | travelled | travelled | ||||||||||||||
60 000 | 60 000 | 60 000 | ||||||||||||||
Distance | Distance | Distance | ||||||||||||||
40 000 | 40 000 | 40 000 | ||||||||||||||
20 000 | 20 000 | 20 000 | ||||||||||||||
0 | 0 | 0 | ||||||||||||||
0 | 200 | 400 | 600 | 800 | 0 | 200 | 400 | 600 | 800 | 0 | 200 | 400 | 600 | 800 | ||
Orexin neurons (N) | Orexin neurons (N) | Orexin neurons (N) |
12-h Light - Sham-Veh - D5-21 | 12-h Light OX-B-SAP-VehD5-21 | 12-h Light OX-B-SAP-MazD5-21 | |||||||||||||||||||||||||||||||||||||||||||
40 000 | r = -0.355 - p = ns | 40 000 | 40 000 | ||||||||||||||||||||||||||||||||||||||||||
r = 0.097 - p = ns | |||||||||||||||||||||||||||||||||||||||||||||
(cm) | 30 000 | (cm) | 30 000 | (cm) | 30 000 | r = 0.528 - p = ns | |||||||||||||||||||||||||||||||||||||||
travelled | 20 000 | travelled | 20 000 | travelled | 20 000 | ||||||||||||||||||||||||||||||||||||||||
Distance | Distance | Distance | |||||||||||||||||||||||||||||||||||||||||||
10 000 | 10 000 | 10 000 | |||||||||||||||||||||||||||||||||||||||||||
0 | 0 | 0 | |||||||||||||||||||||||||||||||||||||||||||
0 | 200 | 400 | 600 | 800 | 0 | 200 | 400 | 600 | 800 | 0 | 200 | 400 | 600 | 800 | |||||||||||||||||||||||||||||||
Orexin neurons (N) | Orexin neurons (N) | Orexin neurons (N) | |||||||||||||||||||||||||||||||||||||||||||
Pearson correlation test: r and p values.
Conditions: T°= 22.0 ± 1.5°C, Hygrometry= 50 ± 30%, Air renewal= 12-25 vol/h, Lighting= 20-30 Lux, Day/night cycle= 12h/12h, Food: | |
Rat-mouse A04 (ad libitum), Drink: Tap water (ad libitum) | |
OX-B-SAPSupplier: Advanced Targeting Systems (ATSBIO); Vehicle: Veh; Administration: Bilateral intracerebral infusion in LH; Doses: | |
Experiment 1A: 490 ng, Experiment 1B: 90, 180 ng, Experiment 2: 90 ng; Application: 1, Volume: 0.5 µL; Preparation: Dissolved in | |
Drugs | PBS, stored at -20°C, used within 2 days, on ice during tests; |
Mazindol Supplier: GreenPharma, Batch Y7391258; Vehicle: HCl 0.1N + 0.9% NaCl + NaOH 0.1N; Administration: Oral gavage (p.o.), | |
some i.p.; Doses: Experiment 1: 0.25, 0.5, 1 mg/kg, Experiment 3: 0.5 mg/kg; Application: 1, Volume: 1 ml/kg; Preparation: Stock | |
solution at -80°C for 6 weeks, ambient temperature during test | |
Pre-surgery: Buprecare 0.03 mg/kg; Anesthesia: Isoflurane; Stereotaxic surgery in standard frame (David Kopf, USA); Coordinates: 3.3 | |
Surgery | mm posterior to bregma, 1.6 mm lateral to sagittal suture, 8.8 mm beneath brain surface; Injection: Veh (Sham) or OX-B-SAP (490 ng, |
180 ng, 90 ng); Post-surgery: Ringer Lactate 1 ml s.c., Metacam 2 mg/kg; Follow-up: Ringer Lactate 1 ml s.c., Metacam 1 mg/kg up to | |
5 days if necessary | |
Recording of | Equipment: Plexiglas open-fields (42 cm L, 42 cm W, 40 cm H) with infrared photobeam detection systems (Acti-track, LSI Leticca, |
Circadian | Panlab); Conditions: Floor covered with litter, free access to food and water; Data: Distance traveled recorded every 15 min for 24-h |
Activity | period, starting at dark period; Read-outs: Distance during 24-hr,12-hr dark, 12-hr light, each 3-hr, each 1-hr period |
Conclusion
Mazindoladministered at 3mg/kg after OX-B-SAP-inducedlesions (90 ng) in the LHsignificantly mitigates thereduction incircadian activitytypically ledby the lesions.By Day 21, mazindol not onlyrestores the activitylevels to normal butexceeds those of the Shamgroup during the dark phase. Thisindicates that mazindol has astrong protective effect against the activitydisruptions ledby thedestruction oforexin cells in the LH,potentially offering atherapeutic approach to counteract
narcolepticsymptoms inducedbyorexin cell loss.
Mazindol per osadministered exhibitspotential interaction with theorexin system, asevidenced by itseffects at different dosages in the rat model withOX-B-SAP-inducedlesions.At a higher dose (3mg/kg), mazindolsignificantly increases circadian activity, suggesting itspotential utility intreating disorders like narcolepsy, where orexin system disruption leadsto decreased activity andwakefulness. The lack ofeffect ornegative impactat lower doses (1mg/kg) underscores theimportance ofdosage in achievingtherapeuticbenefitsthroughpotential"orexinergicmechanisms". Thisrelationshipsuggeststhat mazindolmightworkby eitherdirectly or indirectlymodulatingorexinreceptors or the pathwaysinfluencedby the orexinsystem.
Figure 1. Time schedule of Experiment 1A and Experiment 1B
Figure 2. Time schedule of Experiment 2
Comprehensive Timeline of Orexin Research
Beginning | Surgery | ||||
of | OXB-SAP | ||||
reversed | lesion | ||||
light/dark | or | Non-lesioned rats only (Sham: | |||
cycle | Sham lesion | N=7; non-operated: N=2) | |||
Effect of Mazindol i.p. (1; 3 | |||||
1 i,p. administration / day of vehicle | mg/kg) or p.o. (3; 10 mg/kg) | ||||
D-15 | D-4 | D-3 | D-2 | D-1 | D 0 | D 1 | D 2 | D 3 | D 4 | D 5 | D 6 | D 7 | D 15 - D 22 | |||||||||||||||||||||||||||||||||||||||
2 × 24-hr LMA | 2 × 24-hr LMA | 8 × 24-hr LMA | ||||||||||||||||||||||||||||||||||||||||||||||||||
Beginning | Surgery | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
of | OXB-SAP lesion | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
reversed | or | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
light/dark | Sham lesion | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
cycle | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 p.o. administration / day of vehicle | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
D-15 | D-4 | D-3 | D-2 | D-1 | D 0 | D 1 | D 2 | D 3 | D 4 | D 5 | D 6 | D 7 | D 8 | D12 | D13 | D14 | D15 | D19 | D20 | D21 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2 × 24-hr LMA | 4 × 24-hr LMA | 4 × 24-hr LMA | 3 × 24-hr LMA |
Legend: x24-hr LMA" = x consecutive 24-hr locomotor activity recording
Beginning | Surgery | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
of | OXB-SAP lesion | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
reversed | or | Brain | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
light/dark | Sham lesion | collection | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
cycle | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 p.o. administration / day of mazindol (1; 3 mg/kg) or vehicle | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
D-15 | D-3 | D-2 | D-1 | D 0 | D 1 | D 2 | D 3 | D 4 | D 5 | D 6 | D 7 | D 8 | D12 | D13 | D14 | D15 | D19 | D20 | D21 | D22 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2 × 24-hr LMA | 4 × 24-hr LMA | 4 × 24-hr LMA | 3 × 24-hr LMA |
Figure 3. Surgery in OX-B-SAP lesioned rat
Experiment 1A: OX-B-SAP 490 ng; Experiment 1B: OX-B-SAP 90 ng and
180 ng; Experiment 2: OX-B-SAP 90 ng injection in LH
Sleep-inducing potential of orexin reported in
the treatment of | Primary | ||||
dipsomania | observations on | ||||
Orexin introduced | (Brunton L.) | hypothalamus | |||
lesions in monkeys | |||||
as a pharmacological | highlighting its role | ||||
agent enhancing | in behavior and | ||||
vigilance and | emotional responses | ||||
appetite | (Ranson S.W.) | ||||
(Penzoldt F.) | |||||
1890 | 1891 | 1910 | 1936 | 1939 | 1967 |
Orexin tannate | Discovery by | ||||
efficacy in anemia | William Houlihan: | ||||
and cachexia, | a patent filed by | ||||
highlights its | Sandoz Inc. for | ||||
stimulating effects on | compounds including | ||||
appetite (Smith W.) | mazindol, initially | ||||
studied for its anti- |
inflammatory and/or anticonvulsant and appetite-regulating properties
First significant reports on | |
mazindol highlighting its | Discovery of a |
effectiveness in treating | |
narcolepsy with cataplexy and | mutation in the |
providing therapeutic benefits | hypocretin |
comparable to or greater than | receptor 2 (OX2R) |
those of amphetamines, but | gene causing |
without serious side effects | narcolepsy with |
associated (Parkes, J.D., | cataplexy in dogs |
Schachter, M. & Alvarez B.) | (Lin L., Mignot E.) |
1973 | 1976 | 1979 | 1985 | 1991 | 1998 | 1999 |
Pharmacological | Action of mazindol | Co-discovery by two | ||||
action of mazindol | on lateral | independent teams and | ||||
via cerebral | hypothalamic | designation of orexin for | ||||
norepinephrine | neurons is | hypothalamus-specific peptides | ||||
metabolism has | independent of | (hypocretin) with | ||||
moderate activity | dopaminergic | neuroexcitatory activity, and | ||||
on the CNS and | processes | their receptors, crucial for the | ||||
anorexia in animal | (Sikdar S.K.) | regulation of sleep and appetite | ||||
models (Griffith, J. | (Peyron C., de Lecea L., & | |||||
& Gogerty, J.H.) | Sakurai T., Yanagisawa M.) |
Pathophysiological hypothesis | Serum orexin A levels are significantly lower in drug-naive children | ||||||||||||
Relationship identified | suggesting dysfunction in the | ||||||||||||
orexin system related to ADHD | with ADHD, particularly in the inattentive subtype (Baykal S.) | ||||||||||||
Orexin-induced | between hypocretin (orexin) | and affecting areas controlling | |||||||||||
neurons and CSF hypocretin | wakefulness and reward | Mazindol | Introduction and clinical | Irregular sleep | |||||||||
hyperlocomotion | (orexin-A) levels in | Introducing Dual | processing (Cortese S., Konofal E.) | ||||||||||
and stereotypy in | narcolepsy: | Combination use in | trials of TAK-925 and | patterns and higher | |||||||||
rats are | Neurodegeneration of orexin | Orexin Receptor | First report of Yan7874 as | ADHD treatment | TAK-994 as selective | daytime sleepiness | |||||||
mediated by the | neurons leading to significant | Antagonists | (either as | OX2R agonists, aiming to | in ADHD patients | ||||||||
dopaminergic | reductions of orexin-A level | (DORA), showing | OX1 and OX2 receptors | monotherapy or in | treat narcolepsy with | found and | |||||||
system in the | in CSF is correlated with | potential to treat | agonist exhibiting receptor- | combination with | promising results, | correlated with | |||||||
ventral | increased REM sleep and | insomnia by | independent cytotoxicity, | other compounds) | though some trials were | higher energy drink | |||||||
tegmental area | impaired orexin release | blocking both | which limits its therapeutic | US8293779 B2; | halted due to hepatic | consumption and | |||||||
(Nakamura T.) | during wakefulness | orexin receptors | potential | patent granted | signal | serum orexin levels | |||||||
(Gerashchenko D., Mignot E.) | (Yanagisawa M.) | (Konofal E.) | (Takeda, 2016-2023) | (Sungur M.) | |||||||||
2000 | 2001 | 2003 | 2004 | 2006 | 2008 | 2010 | 2012 | 2014 | 2016 | 2017 | 2018 | 2019 | |
Sleepiness-induced | Effects of hypocretin-2- | Demonstration | First orexin-2 | Studied reporting the | NLS Pharmaceutics | NLS Pharmaceutics | |||||||
receptor agonist | effects of mazindol, | received a patent | announced a mechanism | ||||||||||
hyperlactivity in | saporin (OX-B-SAP) on | that orexin | with | amphetamine | approval and began | of action on orexin system | |||||||
children with | sleep and neuronal loss | peptides prevent | anti-obesity activity | modafinil and | development of | and positive phase 2 data | |||||||
ADHD: First report | in rats: A primary link | cataplexy and | discovered: Initial in | modafinil analog | mazindol | for mazindol extended- | |||||||
on objective | between severity of | improve | vitro metabolism | compounds on | IR/SR multilayer tablet | release (ER) in adults with | |||||||
somnolence | narcolepsy symptoms | wakefulness in an | and pharmacokinetic | impulsive behavior in | for the treatment of | ADHD, demonstrating | |||||||
measured in ADHD | and orexin neuronal loss | orexin neuron- | studies | juvenile Wistar rats | ADHD | significant improvement | |||||||
(Lecendreux M., | (Gerashchenko D.) | ablated model of | with BLX-1026 | subjected to the T- | (US11207271B2; | in symptoms (Wigal T., | |||||||
Konofal E.) | narcolepsy in mice | (Mukherjee A., Sen | Maze procedure | patent granted, 2021), | Konofal E.) | ||||||||
(Mieda M.) | A., Dey B.) | (Bizot J.C., Konofal E.) |
Significant role | Disruption of OX2R in dopamine | |
neurons is found to increase arousal, | ||
found of orexin in | improve cognitive performance, but | |
sleep disorders | impair inhibitory control and further | |
like narcolepsy, | evidence for OX2R modulation by | |
highlighting | mazindol is also provided (Tafti M.) | |
common | ||
symptoms with | Introduction by Centessa | |
ADHD such as | ||
Pharmaceuticals of novel selective | ||
disrupted sleep | ||
OX2R agonists, sulfonamide- | ||
patterns and | ||
derivatives (similar to Alkermes, | ||
impaired cognitive | ||
Sumitomo, Merck and Takeda) aimed | ||
abilities (Barateau | ||
at treating sleep disorders, including | ||
L., Dauvilliers Y.) | ||
narcolepsy | ||
2022 | 2023 | 2024 |
Exploration of | NLS Pharmaceutics | |
announced a | Introduction by Aexon | |
orexin action on | ||
significant | Labs of First-in-Class | |
dopaminergic | ||
improvement in | non-sulfonamide | |
systems | ||
narcolepsy with | Dual Orexin Receptor | |
modulating theta | ||
cataplexy in adults | Agonists (DOXA) and | |
during REM sleep | ||
with mazindol ER (3 | their potential use for | |
and wakefulness, | ||
mg/day) in the | the treatment and/or | |
affecting | ||
POLARIS phase 2 | prevention of | |
attentional | ||
program versus | neurological | |
processes and | ||
placebo for both | diseases (e.g. narcolepsy | |
providing | ||
primary and | with cataplexy) | |
neurobiological | ||
secondary endpoints | (PCT/EP2023/088020) | |
insights into | ||
and announces the | ||
ADHD | ||
FDA approval for |
pathophysiology | AMAZE phase 3 |
(Bandarabadi M.) | |
program | |
Attachments
- Original Link
- Original Document
- Permalink
Disclaimer
NLS Pharmaceutics AG published this content on 28 May 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 28 May 2024 14:09:06 UTC.