Intranasal insulin treatment restores cognitive deficits and insulin signaling impairment induced by repeated methamphetamine exposure

Abstract

Long-term use of methamphetamine (MA) causes a broad range of cognitive deficits. Recently, it has been reported insulin signaling and mitochondrial biogenesis are involved in cognitive processes. This study aimed to examine whether MA induces cognitive deficits concomitant with insulin signaling impairment and mitochondrial dysfunctions and also intranasal (IN) insulin treatment can reverse cognitive deficits caused by MA. Rats were repeatedly treated with increasing doses of MA (1-10 mg/kg) twice a day for 10 days, and their cognitive functions were assessed using Y-maze, novel object recognition and passive avoidance tasks. The expression of components involved in insulin signaling (IR/IRS2/PI3K/Akt/GSK3β) and mitochondrial biogenesis (PGC-1α, NRF1, and TFAM) was measured in the hippocampus. Therapeutic effects of IN insulin delivery (0.5- IU/day, for 7 days after MA discontinuation) were also investigated in MA-treated animals. Our results showed that repeated MA exposure induced cognitive deficits, and led to insulin signaling impairment and mitochondrial dysfunction. Interestingly, IN insulin treatment reduced MA-induced cognitive impairments possibly through activating insulin signaling, particularly PI3K/Akt/GSK3β pathway, and mitochondrial biogenesis. Thus, insulin and insulin signaling pathway can be considered as useful targets for the treatment of abnormalities associated with MA abuse.

Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse

“…3,7–9,13,15,18–20,25,28–37 Herein we show that IN administration achieves insulin exposure in the brain similar to SC administration of the same dose (2.4 IU), but it achieves significantly lower peripheral exposure, preventing severe hypoglycemia. Repeated IN dosing of 2.4 IU insulin was also well tolerated and resulted in increased concentrations of glucose and phosphorylated energy substrates in the brain, a potentially neuroprotective and pro-cognitive profile.…”

“…A growing body of preclinical and clinical evidence suggests that delivery of insulin to the brain may prevent neuronal damage and improve cognition in a broad range of conditions associated with cognitive impairment including diabetes, 1,2 substance abuse, 3 stroke, 4,5 postoperative cognitive dysfunction, 6,7 developmental delay, 8,9 Parkinson’s disease, 10 bipolar disorder, 11 Alzheimer’s disease (AD), 12,13 and HIV-associated neurocognitive disorders (HAND). 14–16 Cognitive deficits in many of these disorders have been linked to oxidative stress in the brain, neuroinflammation, and neurodegeneration.…”

“…18,19 The neuroprotective effects of insulin appear to involve the induction or preservation of brain glucose metabolism and restoration of the energy storage molecules adenosine triphosphate (ATP) and phosphocreatine, 13,20–25 in addition to neurotrophic and anti-inflammatory effects mediated by the direct activation of insulin receptors on neurons. 26,27 When delivered to the brain, insulin has been shown to increase glucose uptake 13,18–20,25,28 and improve cognitive performance in animals, 3,7,15,16,25,29 healthy humans, 30–32 and cognitively impaired patients. 1,2,8,9,11,33–37 Given the absence of robust neuroprotective therapeutics, insulin delivery to the brain has thus emerged as a promising new therapy for multiple neurological and psychiatric disorders.…”

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

“…Triiodothyronine treatment reduced neurodegeneration by restoring insulin signaling in diabetic rats (Prieto‐Almeida et al, ). Intranasal insulin treatment in rats activated insulin signaling which reduced cognitive dysfunction induced by methamphetamine (Beirami, Oryan, Seyedhosseini Tamijani, Ahmadiani, & Dargahi, ).…”

Methamphetamine exposure upregulates the amyloid precursor protein and hyperphosphorylated tau expression: The roles of insulin signaling in SH-SY5Y cell line

“…Acute or chronic METH exposure contributes to a spectrum of toxic effects on the central nervous system (CNS) (Prakash et al, 2017). Long-term exposure to METH causes a range of cognitive deficits (Beirami et al, 2018), which involve several mechanisms. For example, METH exposure has been shown to be associated with neuroinflammation in several brain areas, due to its addictive effect (Wongprayoon and Govitrapong, 2015).…”