Neuropsychological Deficits Chronically Developed after Focal Ischemic Stroke and Beneficial Effects of Pharmacological Hypothermia in the Mouse

Abstract

Stroke is a leading cause of human death and disability, with around 30% of stroke patients develop neuropsychological/neuropsychiatric symptoms, such as post-stroke depression (PSD). Basic and translational research on post-stroke psychological disorders is limited. In a focal ischemic stroke mouse model with selective damage to the sensorimotor cortex, sensorimotor deficits develop soon after stroke and spontaneous recovery is observed in 2-4 weeks. We identified that mice subjected to a focal ischemic insult gradually developed depression/anxiety like behaviors 4 to 8 weeks after stroke. Psychological/psychiatric disorders were revealed in multiple behavioral examinations, including the forced swim, tail suspension, sucrose preference, and open field tests. Altered neuronal plasticity such as suppressed long-term potentiation (LTP), reduced BDNF and oxytocin signaling, and disturbed dopamine synthesis/uptake were detected in the prefrontal cortex (PFC) during the chronic phase after stroke. Pharmacological hypothermia induced by the neurotensin receptor 1 (NTR1) agonist HPI-363 was applied as an acute treatment after stroke. A six-hr hypothermia treatment applied 45 min after stroke prevented depression and anxiety like behaviors examined at 6 weeks after stroke, as well as restored BDNF expression and oxytocin signaling. Additionally, hypothermia induced by physical cooling also showed an anti-depression and anti-anxiety effect. The data suggested a delayed beneficial effect of acute hypothermia treatment on chronically developed post-stroke neuropsychological disorders, associated with regulation of synaptic plasticity, neurotrophic factors, dopaminergic activity, and oxytocin signaling in the PFC.

Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

“…In light of this, there is now growing evidence demonstrating that NT(8-13) analogs induce regulated reduction of body and brain temperatures through activation of the NTS1 receptor subtype (Liu et al, 2016). Indeed, administration of the NTS1 agonists, NT69L, PD149163, HPI-201, or HPI-363, produced mild hypothermia and improved the neurological outcomes compared with that of results from external cooling (Katz et al, 2001;Choi et al, 2012;Wei et al, 2013;Lee et al, 2014Lee et al, , 2016Gu et al, 2015;Xue et al, 2017;Zhao et al, 2020;Zhong et al, 2020). Here, we therefore determined the ability of these specific pairs of NT(8-13) analogs to regulate the body temperature and evaluated the contribution of the receptor binding affinity and peptide plasma stability on the hypothermic activity.…”

“…More recently, a series of studies has highlighted the benefit of achieving regulated reduction of body temperature using NTS1 agonists in different clinically relevant situations. For instance, systemic administration of NT69L, PD149163, or HPI-201 (formally ABS-201) produced mild hypothermia and exerted neuroprotective effects after ischemic stroke, intracerebral hemorrhage, resuscitation from cardiac arrest, and traumatic brain injury (Katz et al, 2001;Choi et al, 2012;Wei et al, 2013;Gu et al, 2015;Lee et al, 2016;Xue et al, 2017;Zhao et al, 2020;Zhong et al, 2020).…”

Potential Biochemical Mechanisms of Brain Injury in Diabetes Mellitus

“…[18,114]. It should be pointed out that post-stroke depression/anxiety is also a common neuropsychological consequence of IS [115]. In addition, brain edema is the primary cause of IS mortality.…”

Intra-arterial Cold Saline Infusion in Stroke: Historical Evolution and Future Prospects

“…Acute ischemic stroke (AIS) is an increasingly prevalent threat to human health [ 1 , 2 ]. A recent epidemiological review concluded that stroke accounts for nearly 5% of all disability-adjusted life years and 10% of all deaths worldwide [ 3 , 4 ].…”