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Cognitive Effects of Colostral-Val Nonapeptide in Aged Rats

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Cognitive Effects of Colostral-Val Nonapeptide in Aged Rats Behavioural Brain Research 118 (2001) 201–208 www.elsevier.com/locate/bbr Research report Cognitive effects of Colostral-Val nonapeptide in aged rats Piotr Popik a,*, Zdzislaw Galoch a, Maria Janusz b,Jo´zef Lisowski b, Jerzy Vetulani a a Institute of Pharmacology, Polish Academy of Sciences, 12 Sme˛tna Street, 31–343 Krako´w, Poland b Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12 Street, 53–114 Wrocl*aw, Poland Received 26 May 2000; received in revised form 8 September 2000; accepted 8 September 2000 Abstract Colostrinin, a complex of polypeptides derived from sheep colostrum retards the progress of Alzheimer’s disease and facilitates acquisition and retrieval of spatial memory in aged rats. Here we investigated the cognitive effects of colostrinin-derived nonapeptide (Colostral-Val nonapeptide, CVNP) in aged rats that demonstrated learning deficits. Administered for 14 days, CVNP did not affect the acquisition of spatial learning or memory retrieval in the Morris water maze. As a result of reversal learning, placebo treated rats shifted searching behavior and swam less in the area of original platform position and more in the area of recent platform position, suggesting formation of the new spatial map. CVNP treated rats did not change the searching pattern and still investigated the area that contained ‘original’ escape platform, suggesting that CVNP treatment delays the extinction of spatial memory. In another experiment, CVNP administered for 8 days did not influence the acquisition of the active avoidance task, but significantly delayed its extinction. The present findings indicate that colostrinin-derived nonapeptide may delay the extinction of long-term memories. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Memory; Learning; Alzheimer’s disease; Colostrum; Colostrinin; Proline-rich polypeptide complex; Colostral-Val nonapeptide; Morris water maze; Active avoidance 1. Introduction in the first period of life. One of the immunologically active agents from ovine colostrum was isolated by Investigation of the cognitive effects of peptides has a Janusz et al. [15–17] and was characterized as an 18 long history. In the 1960s, De Wied found that removal kDa polypeptide, built of three 6 kDa subunits, rich in of the posterior lobe of the pituitary in rats impaired proline (22%) and non-polar amino acids. The prepara- the maintenance of avoidance behavior and that this tion was subsequently found to be rather a complex of deficit could be restored by treatment with vasopressin proline-rich polypeptides (PRP). The polypeptide com- [6]. These and other findings resulted in the appearance plex, named colostrinin, was characterized as a new of the ‘neuropeptide’ concept in the 1970s and a hy- cytokine [14]. Recently, the immunoactive properties of pothesis that peptides are implicated in learning and the human analog of ovine colostrinin were described memory processes. This hypothesis was later supported [11,21]. Colostrinin induces maturation and differentia- by numerous findings demonstrating that various pep- tion of murine thymocytes and affects humoral and tides affect learning and memory processes in several cellular immune reactions, both in vivo and in vitro behavioral paradigms (for reviews, see Refs. [7,30]). [15,31]. Colostrum, the early milk produced during puerperal By digestion of colostrinin with chymotrypsin, a non- period, plays an essential role in the survival of new- apeptide fragment of mol.% wt.% 1000, with a sequence borns and is the main source of immunological defense of Val–Glu–Ser–Tyr–Val–Pro–Leu–Phe–Pro was isolated [29]. This Colostral-Val nonapeptide (CVNP), * Corresponding author. Tel.: +48-12-6374630; fax: +48-12- 6374500. both isolated from chymotryptic digest as well as ob- E-mail address: [email protected] (P. Popik). tained by the chemical synthesis [32], showed the full 0166-4328/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S0166-4328(00)00323-5 202 P. Popik et al. / Beha6ioural Brain Research 118 (2001) 201–208 spectrum of immunotropic activities of colostrinin. weight 485–500 g), obtained from the colony of the CVNP showed a strong effect on the primary and Institute of Immunology and Experimental Therapy, secondary immune response against SRBC (T-cell de- were housed under standard laboratory conditions pendent antigen) in mice [18]. Whereas colostrinin at (lights on at 06:00 h, lights off at 18:00 h; room concentrations of 1–100 mg/ml induced production of temperature 2391°C) with pelleted food and tap water interferon and tumor necrosis factor a in human pe- available ad libitum. Rats were kept in plastic cages ripheral blood leukocytes as well as in the whole blood measuring 58×37×19 (four to five rats per cage). cell cultures, CVNP was considerably less active as a cytokine inducer. Thus, significant levels of interferon 2.2. Drugs and tumor necrosis factor were induced by 100 mg/ml of CVNP, but lower concentrations were found to be CVNP, the active nonapeptide fragment of ineffective [13]. Similarly, it was also reported that colostrinin (Val–Glu–Ser–Tyr–Val–Pro–Leu–Phe– cytokine-inducing activity of CVNP in cultures of hu- Pro) was synthesized by the solid-phase method [32] man whole blood cells was considerably lower than that and kindly provided by Professor G. Kupryszewski, of colostrinin [33]. Institute of Chemistry, University of Gdansk, Poland. Among the most prominent consequences of normal Physiological saline served as placebo. All injections and pathological aging in humans are cognitive deficits, were done i.p. in a volume of 1 ml/kg. The selection of including learning impairment and delayed amnesia. the dose for current investigation was based on our Perhaps the most severe form of the senile dementia is previous report [23] and immunotropic effects of Alzheimer’s disease, which is associated with numerous colostrinin and CVNP in animals [18]. Since CVNP in pathophysiological alterations of the CNS. Pathophysi- immunological tests appears to be much less potent ological changes in Alzheimer’s patients include, among than colostrinin, and since we previously used doses of others, accumulation of b-amyloid plaques and neurofi- 4–20 mg per rat (:8–40 mg/kg), for the current exper- brillary tangles [12]. In addition to the profound im- iment the dose of 50 mg per rat (100 mg/kg) was pairment in cholinergic transmission, alterations in the selected. CVNP was dissolved in sterile physiological function of cytokines and other factors associated with saline and the dilution was divided into 7-ml aliquots immune reactions have been reported [2,5,9], (see Ref. that were stored at −20°C. A fresh aliquot was used [10] for the recent review). each day. The possibility that immunological factors play a key role in Alzheimer’s disease was investigated in the 2.3. Morris water maze double-blind, placebo controlled clinical experiment. As measured by the Mini Mental State score and the 2.3.1. Apparatus recent memory test, 11 out of 16 patients undergoing A gray metal circular pool (180 cm in diameter, 50 three to six cycles of therapy consisting of oral adminis- cm in height) was filled to a height of 25 cm with tration of colostrinin (100 mg every second day in one lukewarm (22°C) tap water that was changed every day, cycle lasting for 3 weeks) significantly improved their as described previously [22,23]. Curtains, bright lamps cognitive functioning [19]. Recent study from our labo- and other stimuli around and above the pool provided ratory indicate that colostrinin produced a beneficial numerous stable extra-maze cues. effect on spatial learning in aged rats [23]. We found that colostrinin at the dose of 4 mg per rat facilitated 2.3.2. Procedure the acquisition of spatial learning in the Morris water The behavioral procedure consisted of pre-training maze of 13- but not 3-month-old rats. In addition, the (days 1–14), the first ‘transfer test’ (day 15), training to dose of 4 mg per rat improved incidental learning the new platform position (reversal learning, day 16) (habituation test) in 13-month-old rats. The present and the second ‘transfer test’ (day 17). During pre- study was carried out to investigate the possibility that training (one trial per day), rats were injected with colostrinin-derived nonapeptide (Colostral-Val non- placebo or 100 mg/kg of CVNP 30 min before each of apeptide, CVNP) sharing colostrinin’s immunotropic the swimming trials and were required to find the activity and characterized to a greater extent may have platform located in the initial (NE or SW) quadrant. similar effects on learning and memory in rats. Since day 15, no injections were given. During the first ‘transfer test’, rats swam for 1 min in the pool without the platform. On day 16, rats were trained to find the 2. Materials and methods platform positioned in the opposite (SW or NE) quad- rant. This was accomplished with four trials, with the 2.1. Animals inter-trial interval of 30 s. The second ‘transfer test’ was carried out similarly to the first, with the platform Male Wistar rats :16–19 months of age (body removed. For one half of the subjects, the platform was P. Popik et al. / Beha6ioural Brain Research 118 (2001) 201–208 203 placed in the NE quadrant during pre-training and in quadrant. The time a rat spent in the ‘initial’ quadrant the SW quadrant during training. For the other half, was divided by that sum. This measure allowed the the platforms were placed in opposite quadrants. assessment of the relative preference for the pre-training The swimming trial consisted of manually placing a quadrants (0–100%). The difference between the rela- rat into the water facing the wall of the pool, at one of tive preference for the first ‘transfer test’ and for the two starting positions (SE or NW) around the pool second ‘transfer test’ was used as the index of memory perimeter.
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