Biology subjects

Pan, H.-L.

Publications and source records attributed to Pan, H.-L..

4 recordsLinked to original sources

bioRxiv2026

Multispecies translational evaluation of an NMDA receptor modulator reveals analgesic, autonomic-stabilizing, and stress mitigating effects without evidence of abuse liability

CNS4 is an agonist concentration-biased NMDAR modulator exhibiting GluN2 subtype-dependent activity. Here we evaluated the translational pharmacology of CNS4 across mice, rats, and client-owned surgical oncology dogs. In mice, CNS4 did not produce conditioned place preference, indicating lack of reward liability. CNS4 produced dose-dependent reductions in locomotor activity without motor impairment on accelerating rotarod testing. CNS4 also maintained body temperature 0.5 to 1 degree Celsius above the vehicle group in mice and dogs, consistent with NMDAR-dependent thermoregulatory activity and contrasting with hypothermic effects reported for NMDAR channel blockers such as ketamine. In fear-conditioning paradigms, CNS4 did not impair fear learning, memory consolidation, or fear expression. CNS4 reduced acute stress-induced sucrose preference, suggesting modulation of stress-responsive neural circuits. In a rat spinal nerve ligation model of neuropathic pain, both single-dose and three-day repeated CNS4 administration significantly reversed mechanical, pressure, and thermal hypersensitivity, supporting analgesic efficacy with no apparent evidence of rapid tolerance development. In client-owned surgical oncology dogs undergoing standard veterinary procedures, preliminary findings from 14 dogs (8 CNS4-treated, 6 vehicle-treated) demonstrated stable intraoperative mean arterial pressure and heart rate. Postoperatively, CNS4-treated dogs exhibited normal physiological recovery, with respiratory rate, heart rate, and body temperature returning toward the normal canine range, and required approximately 8% less propofol for anesthetic induction. Collectively, these findings support CNS4 as a novel NMDAR modulator with thermoregulatory, anti-agitative, analgesic, and autonomic-stabilizing properties without evidence of abuse liability, supporting continued translational development for neuropathic pain and possibly neuropsychiatric disorders.

pharmacology and toxicology↗

bioRxiv2026

Angiotensin AT1 Receptors Promote Age-Dependent Expansion of Presympathetic Networks in Spontaneously Hypertensive Rats

Heightened sympathetic outflow is a major contributor to the development of hypertension. The hypothalamic paraventricular nucleus (PVN) and the rostral ventrolateral medulla (RVLM) are critical regions for generating and regulating sympathetic activity associated with hypertension. Although presympathetic neural circuitry in the healthy brain is well characterized, it remains unclear whether these pathways undergo alterations in hypertension. Here, we determined presympathetic neural circuits by injecting pseudorabies virus (PRV), a transsynaptic retrograde tracer, into the adrenal gland of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Adult SHR exhibited a significantly greater number of PRV-labeled neurons in the PVN and RVLM, but not in the spinal intermediolateral column, compared with WKY. In contrast, the numbers of PRV-labeled neurons in the PVN and RVLM were comparable between young, prehypertensive SHR and age-matched WKY. Remarkably, long-term treatment with losartan--a brain-penetrant angiotensin II AT1 receptor antagonist-- initiated in young, prehypertensive SHR blunted the age-dependent hypertension development and reversed the increase in neuronal labeling in both the PVN and RVLM. However, losartan treatment had no effects in WKY. Additionally, electrophysiological recordings showed an elevated frequency of miniature excitatory postsynaptic currents in PVN presympathetic neurons of SHR, which was also normalized by long-term losartan treatment. These findings reveal an age-dependent expansion of presympathetic neuronal connectivity from the hypothalamus and brainstem to the adrenal gland during hypertension development in SHR. Enhanced AT1 receptor activity contributes to hypertension by increasing active glutamatergic synaptic input and promoting the recruitment of additional presympathetic neurons in the hypothalamus and brainstem. Key Points1. The numbers of neurons labeled by PRV injected into the adrenal gland are increased in the PVN and RVLM, but not in the spinal cord IML, in adult SHR compared to normotensive WKY. 2. The numbers of neurons in the PVN, RVLM, and spinal cord labeled by PRV injected into the adrenal gland are comparable in young, prehypertensive SHR and age-matched WKY. 3. Losartan treatment, initiated at a young age, blunts the hypertension development and reverses the increased numbers of PRV-labeled neurons in the PVN and RVLM of adult SHR but has no such effects in WKY. 4. The active glutamatergic synapses in PVN presympathetic neurons are elevated in adult SHR, and this elevation is reversed by long-term losartan treatment.

neuroscience↗

bioRxiv2024

Memantine Inhibits Calcium-Permeable AMPA Receptors

Memantine is an US Food and Drug Administration (FDA) approved drug that selectively inhibits NMDA-subtype ionotropic glutamate receptors (NMDARs) for treatment of dementia and Alzheimers. NMDARs enable calcium influx into neurons and are critical for normal brain function. However, increasing evidence shows that calcium influx in neurological diseases is augmented by calcium-permeable AMPA-subtype ionotropic glutamate receptors (AMPARs). Here, we demonstrate that these calcium-permeable AMPARs (CP-AMPARs) are inhibited by memantine. Electrophysiology unveils that memantine inhibition of CP-AMPARs is dependent on their calcium permeability and the presence of their neuronal auxiliary subunit transmembrane AMPAR regulatory proteins (TARPs). Through cryo-electron microscopy we elucidate that memantine blocks CP-AMPAR ion channels in a unique mechanism of action from NMDARs. Furthermore, we demonstrate that memantine reverses a gain of function AMPAR mutation found in a patient with a neurodevelopmental disorder and inhibits CP-AMPARs in nerve injury. Our findings alter the paradigm for the memantine mechanism of action and provide a blueprint for therapeutic approaches targeting CP-AMPARs.

biophysics↗

bioRxiv2024

Nerve injury downregulates δ-opioid and cannabinoid CB1 receptor genes through REST in primary sensory neurons

The transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of 4 opioid receptor (Oprm1, Oprd1, Oprl1, Oprk1) and the cannabinoid CB1 receptor (Cnr1) genes in the DRG regulate nociception. In this study, we determined the role of REST in the control of their expression in the DRG induced by spared nerve injury (SNI) in both male and female mice. Transcriptomic analyses of male mouse DRGs followed by quantitative reverse transcription polymerase chain reaction analyses of both male and female mouse DRGs showed that SNI upregulated expression of Rest and downregulated mRNA levels of all 4 opioid receptor and Cnr1 genes, but Oprm1 was upregulated in female mice. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions of Oprm1 and Cnr1. Chromatin immunoprecipitation analyses indicated differing levels of REST at these promoters in male and female mice. Full-length Rest conditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression of Oprd1 and Cnr1 in the DRG in both male and female mice. Our results suggest that nerve injury represses the transcription of Oprd1 and Cnr1 via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain.

neuroscience↗