Gerashchenko D, Greco MA, Salin-Pascual R, Kilduff TS, Lappi DA, Shiromani PJ (2000) Orexin-B conjugated to saporin lesions LH and TMN neurons and produces narcoleptic-like sleep in rats. Neuroscience 2000 Abstracts 566.27. Society for Neuroscience, New Orleans, LA.

Summary: A dysfunction of the hypocretin/orexin (Hcrt/Ox) system was recently linked with the sleep disorder, narcolepsy. To provide an experimental method that could be used to inactivate Hcrt/Ox receptor bearing neurons, we linked the toxin, saporin, to the orexin receptor binding ligand, orexin-B. Eighteen male Sprague-Dawley rats (400-450 g) were administered orexin-saporin (0.5 ul; 490 ng) to the lateral hypothalamus (LH) (where Hcrt/Ox containing neurons are located) or tuberomammillary nucleus (TMN) (where Hcrt/Ox receptor containing neurons are present) and sleep was recorded for 3 weeks. A significant reduction in the numbers of TMN and Hcrt/Ox neurons in the LH was detected 3 to 5 days after toxin administration and complete loss occurred by 2 weeks. Rats with extensive cell loss exhibited more REM sleep, nonREM sleep, and multiple sleep onset REM periods during the night. In the only two available animal models of human narcolepsy, the dysfunction in the orexin system is inherited and in the entire animal which makes it difficult to localize specific brain regions or circuits underlying narcolepsy. Orexin-saporin provides a method of determining the contribution of a specific Hcrt/Ox innervation in the regulation of behavior.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Millan-Aldaco D, Arias-Carrion O, Palomero-Rivero M, Drucker-Colin R, Murillo-Rodriguez E (2007) Transplant of hypocretin neurons into the lateral hypothalamus of a narcolepsy rat model. Neuroscience 2007 Abstracts 779.2/E4. Society for Neuroscience, San Diego, CA.

Summary: Narcolepsy, a disabling neurological disorder, is characterized by excessive daytime sleepiness, sleeps attacks, sleep fragmentation, and cataplexy. This sleep disorder has been linked to a loss of neurons into the lateral hypothalamus (LH) containing the neuropeptide hypocretin (HCRT). Our group has developed an experimental model in rats that mimics several aberrant behaviours observed in human narcolepsy. The bilateral administration of the neurotoxin hypocretin-2-saporin (HCRT2-SAP) into the LH of rats destroys most of the HCRT neurons (~90%) leading to develop narcolepsy as evaluated using EEG/EMG means. In order to replace the HCRT lost neurons by the local injection of the HCRT2-SAP, a suspension of cells from the hypothalamus obtained from rat pups (3-5 days old) were processed for grafting and stained with GFP. This cell suspension was injected into the LH of lesioned rats and they were sacrificed 21 days post-transplant. The brain was cut and sections containing LH were processed for HCRT immunohistochemistry as well as for the presence of HCRT-immunoflorescence neurons. We were able to differentiate the HCRT transplanted neurons into the LH of lesioned rats. Importantly, they were present at the target area 21 days after implant. These somata were similar in size and appearance to adult rat HCRT-immunoreactive neurons. Our results are very promising since the present study indicates that HCRT neurons obtained from rat pups can be grafted into a host brain and graft survived during 21 days. This experimental approach definitely addresses the possibility to replace HCRT neurons in narcolepsy in order to reverse this disease.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Gerashchenko K, Blanco-Centurion C, Greco MA, Shiromani PJ (2003) Effects of lateral hypothalamic lesion with the neurotoxin hypocretin-2-saporin on sleep in Long-Evans rats. Neuroscience 116:223-235. doi: 10.1016/s0306-4522(02)00575-4

Summary: Recent data has linked narcolepsy to the loss of neurons containing the neuropeptide hypocretin, also known as orexin. The authors wished to investigate whether the variance in severity of narcolepsy could be explained by the extent of loss of these neurons. After injection of 90 or 490 ng of orexin-SAP (Cat. #IT-20) into the lateral hypothalamus, the measurement of several parameters demonstrated the severity of narcolepsy may be linked to the degree of loss of neurons expressing the orexin receptor.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Gerashchenko D, Kohls MD, Greco M, Waleh NS, Salin-Pascual R, Kilduff TS, Lappi DA, Shiromani PJ (2001) Hypocretin-2-saporin lesions of the lateral hypothalamus produce narcoleptic-like sleep behavior in the rat. J Neurosci 21(18):7273-7283. doi: 10.1523/JNEUROSCI.21-18-07273.2001 PMID: 11549737

Summary: Orexin (also knows as hypocretin) peptides are produced exclusively by neurons in the lateral hypothalamus, however non-specific lesioning in this region has not produced narcoleptic-like sleep. Gerashchenko et al. use orexin-SAP (490 ng/0.5 µl; Cat. #IT-20) to specifically eliminate orexin neurons in rats. The treated rats displayed several sleep disturbances found in narcolepsy, including increased slow-wave sleep, and sleep-onset REM sleep periods. The data suggest that orexin-SAP can be used to create a model for narcolepsy in rats.

Related Products: Orexin-B-SAP (Cat. #IT-20), Saporin Goat Polyclonal, affinity-purified FITC-labeled (Cat. #AB-15APFL), Saporin Chicken Polyclonal, affinity-purified (Cat. #AB-17AP)

Gerashchenko D, Salin-Pascual R, Shiromani PJ (2001) Effects of hypocretin-saporin injections into the medial septum on sleep and hippocampal theta. Brain Res 913:106-115. doi: 10.1016/s0006-8993(01)02792-5

Summary: Hypocretin, also known as orexin, neurons are located only in the lateral hypothalamus. Recently, the loss of these neurons was shown to be associated with narcolepsy. The authors used orexin-SAP (100 ng/0.5 µl; Cat. #IT-20) to eliminate parvalbumin and cholinergic neurons (orexin B receptor-expressing) in the rat medial septum. They used 192-Saporin (1 µg/ 1 µl; Cat. #IT-01) to contrast the effect and eliminate only cholinergic neurons (NGF/p75 receptor-expressing). Hippocampal theta activity was completely eliminated in orexin-SAP treated rats by day 12, suggesting that orexin neurons influence cognitive processes critical for survival.

Related Products: 192-IgG-SAP (Cat. #IT-01), Orexin-B-SAP (Cat. #IT-20)

Bhyrapuneni G, Benade V, Daripelli S, Kamuju V, Shinde A, Abraham R, Nirogi R, Jasti V (2019) SUVN-G3031, histamine H3 receptor inverse agonist preclinical evaluation for the treatment of excessive daytime sleepiness in narcolepsy. Neuroscience 2019 Abstracts 502.07. Society for Neuroscience, Chicago, IL.

Summary: Numerous studies have demonstrated that brain histamine plays a crucial role in maintenance of wakefulness, attention, learning and other cognitive processes. SUVN-G3031, a potent histamine H3 receptor inverse agonist is being developed for the treatment of narcolepsy and other sleep related disorders. SUVN-G3031 is one of the lead molecules with hKi of 8.7 nM and has more than 100 fold selectivity against the related GPCRs. SUVN-G3031 exhibited desired pharmacokinetic properties and brain penetration. SUVN-G3031 blocked R-α-methylhistamine induced water intake and increased tele-methylhistamine levels in brain and cerebrospinal fluid. In the present study, SUVN-G3031 was evaluated in brain microdialysis and rodent models of electroencephalography (EEG). SUVN-G3031 was evaluated in brain microdialysis for evaluation of neurotransmitters like acetylcholine, histamine, dopamine and norepinephrine in male Wistar rats. EEG was used to evaluate the effects on sleep/ wake profile in rats and mice.A single oral administration of SUVN-G3031 produced significant increase in acetylcholine, histamine, dopamine and norepinephrine levels in the cortex. SUVN-G3031 produced no change in the dopamine levels of striatum and nucleus accumbens indicating that SUVN-G3031 may not have addiction liabilities. Narcoleptic-like sleep behavior was observed in rats injected with hypocretin-2-saporin in lateral hypothalamus. SUVN-G3031 produced significant increase in wakefulness with concomitant decrease in rapid eye movement (REM) sleep in these animals. These results are in agreement with EEG studies carried out in healthy male Wistar rats. Results from current studies provide strong evidence for the potential of SUVN-G3031 in the treatment of excessive daytime sleepiness associated with narcolepsy. First in human, Phase 1 studies for SUVN-G3031 are completed under US IND and SUVN-G3031 has shown desirable pharmacokinetic profile with safety and tolerability in healthy human volunteers. Phase 2 study for the treatment of excessive daytime sleepiness associated with narcolepsy is currently ongoing in USA.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Kaur S, Thankachan S, Begum S, Liu M, Blanco-Centurion C, Shiromani PJ (2009) Hypocretin-2 saporin lesions of the ventrolateral periaquaductal gray (vlPAG) increase REM sleep in hypocretin knockout mice. PLoS One 4:e6346. doi: 10.1371/journal.pone.0006346

Summary: Not all connections between narcolepsy and orexin are understood, since orexin neurons are located in the lateral hypothalamus and some sleep functions are controlled by the brainstem. This experiment used 16.5 ng injections of orexin-SAP (Cat. #IT-20) into each side of the ventrolateral periaqueductal gray (v/PAG to) examine these connections. The results indicate that loss of orexin neurons in the v/PAG results in loss of inhibitory control over REM sleep, but does not cause cataplexy.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Ocampo-Garces A, Ibanez F, Perdomo G, Torrealba F (2011) Orexin-B-saporin lesions in the lateral hypothalamus enhance photic masking of rapid eye movement sleep in the albino rat. J Sleep Res 20:3-11. doi: 10.1111/j.1365-2869.2010.00864.x

Summary: Photic masking occurs when photic input to the retina interferes with REM sleep. Rats that received 200 ng of orexin-SAP (Cat. #IT-20) into the lateral hypothalamus experienced dramatically less REM sleep during normal light cycles. Placing them in a skeleton photoperiod (brief pulses of light, one in the morning and one in the evening), however, caused REM sleep during the rest phase to return to normal. This data suggests that photic masking may explain some effects of narcolepsy and cataplexy.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Arias-Carrion O, Murillo-Rodriguez E (2009) Cell transplantation: a future therapy for narcolepsy?. CNS Neurol Disord Drug Targets 8:309-314. doi: 10.2174/187152709788921681

Summary: This review covers the current understanding of narcolepsy and discusses the potential for transplants as a therapeutic treatment. Animal models are summarized, including the use of orexin-SAP (Cat. #IT-20) in rats. The review goes on to suggest that production of orexigenic neuroblasts from stem cells may be a useful therapy.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Hernandez-Martinez H, Arias-Carrion O, Drucker-Colin R, Murillo-Rodriguez E (2006) Transplant of hypocretin neurons into the lateral hypothalamus of rats with lesions of the hypocretin neurons. Neuroscience 2006 Abstracts 719.2. Society for Neuroscience, Atlanta, GA.

Summary: Narcolepsy, a disabling neurological disorder is characterized by excessive daytime sleepiness, sleeps attacks, sleep fragmentation, and cataplexy. This sleep disorder has been linked to a loss of neurons containing the neuropeptide hypocretin (HCRT). Our group has developed an experimental model to induce narcolepsy in rats. The bilateral administration of the neurotoxin hypocretin-2-saporin (HCRT2-SAP) into the lateral hypothalamus (LH) of rats destroys the HCRT neurons. Therefore, the loss of HCRT neurons leads to developing narcolepsy. In order to replace the HCRT lost neurons by HCRT2-SAP, a suspension of cells from the posterior hypothalamus of 3-5 days old rat pups were stained with GFP and injected into the LH of lesioned rats. Animals were sacrificed 21 days after transplant, and cryostat-cut coronal sections of the LH sections were examined for presence of HCRT-immunofluorescence neurons. Preliminary data shows that HCRT transplanted neurons into the LH of lesioned rats were present at the target area 21 days after implant. These somata were similar in size and appearance to adult rat HCRT-immunoreactive neurons. Our results indicate that HCRT neurons obtained from rat pups can be grafted into a host brain and graft survives during 21 days. Importantly, our study addresses the possibility to replace HCRT neurons in narcolepsy in order to reverse this disease.

Related Products: Orexin-B-SAP (Cat. #IT-20)